Quinolinecarboxylic acid derivatives, antibacterial agent containing the same

ABSTRACT

Novel quinolinecarboxylic acid derivatives of the formula: ##STR1## wherein Z is ##STR2## or ##STR3## in which R 1  is hydrogen atom, a halogen atom, hydroxy or a lower alkyloxy; R 2  is a halogen atom, hydroxy or a lower alkyloxy; R 3  is a lower alkyl; and R 4  is hydroxy or a di(lower alkyl)amino, and a pharmaceutically acceptable salt thereof, which have excellent antibacterial activities and are useful as an antibacterial agent, a pharmaceutical composition containing the same, and process for preparing the same.

The present invention relates to novel quinolinecarboxylic acidderivatives, an antibacterial agent containing said compound as anactive ingredient, a process for preparing said compound and a novelintermediate compound used for preparing said compound. Moreparticularly, the present invention relates to novel quinolinecarboxylicacid derivatives represented by the following formula (I): ##STR4##wherein Z is ##STR5## or ##STR6## in which R¹ is hydrogen atom, ahalogen atom, hydroxy or a lower alkyloxy; R² is a halogen atom, hydroxyor a lower alkyloxy; R³ is a lower alkyl; and R⁴ is hydroxy or adi(lower alkyl)amino, and a pharmaceutically acceptable salt thereof, anantibacterial agent containing said compound (I) as an activeingredient, a process for preparing said compound (I) and novelintermediate compound used for preparing said compound (I).

PRIOR ART

Since the finding of nalidixic acid as a synthetic antibacterial agent,various quinolinecarboxylic acid derivatives including condensedtricyclic compounds and condensed tetracyclic compounds have hithertobeen examined for aiming at the improvement of an antibacterialactivity. For example, U.S. Pat. No. 4,382,892 discloses condensedtribyclic compounds having a pyrido[1,2,3-de][1,4]benzoxazine ringincluding the following compound (X), and further European PatentPublication No. 286089 (corresponding to U.S. Pat. No. 4,808,584,divisional application thereof U.S. Pat. No. 4,853,469) and Proceedingof the 109th Annual Meetings of the Pharmaceutical Society of Japan,Nagoya 1989, Vol. IV, page 30 disclose condensed tetracyclic compoundshaving a 9,1-epoxymethano-5H-thiazolo[3,2-a]quinoline ring including thefollowing compound (Y). ##STR7##

However, the above publications do not disclose the condensedtetracyclic compounds (I) of the present invention having a9,1-iminomethano-5H-thiazolo[3,2-a]quinoline ring.

Some condensed tetracyclic compounds having9,1-iminomethano-5H-thiazolo[3,2-a]quinoline ring have been disclosed inU.S. Pat. No. 4,971,967 issued on Nov. 20, 1990 which is later than thepriority date (Aug. 30, 1990) of this application. The invention of theabove U.S. patent has been invented by Kondo et al. who are the sameinventors as in the present invention, and further, the U.S. patent doesnot disclose the novel compounds of the formula (I) of the presentinvention.

BRIEF SUMMARY OF THE INVENTION

The present inventors have studied to find novel quinolinecarboxylicacid derivatives having condensed teteracyclic ring and having improvedantibacterial activities and found that the novel quinolinecarboxylicacid derivatives having condensed tetracyclic ring of the formula (I) asdescribed hereinbefore have improved antibacterial activities and areuseful as an antibacterial agent.

An object of the present invention is to provide novelquinolinecarboxylic acid derivatives having condensed tetracyclic ringwhich show improved antibacterial activities. Another object of thepresent invention is to provide an excellent antibacterial agentcontaining said compounds as an active ingredient. Still another objectof the present invention is to provide a process for preparing saidcompounds. A further object of the present invention is to provide novelintermediate compounds used for preparing said compounds.

DETAILED DESCRIPTION OF THE INVENTION

The quinolinecarboxylic acid derivative of the present invention are9,1-iminomethano-5H-thiazolo[3,2-a]quinoline-4-carboxylic acidderivatives of the formula (I) as described hereinbefore and apharmaceutically acceptable salt thereof, which show potentantibacterial activities.

Through the present specification and claims, the term "lower alkyl"denotes a straight chain or branched chain alkyl having 1 to 4 carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,and the like. The di(lower acyloxy)boryl denotes a group consisting ofone boron atom and two acyloxy groups having 2 to 5 carbon atoms of theformula: --B(OCOR³)₂ wherein R³ is as defined above, for examplediacetyloxyboryl, dipropionyloxyboryl, dibutyryloxyboryl, and the like.

Suitable examples of the above cyclic amino group (Z) are2-methylmorpholino, 2-hydroxymethylmorpholino, 2-fluoromethylmorpholino,2-chloromethylmorpholino, 2-methoxymethylmorpholino,2-ethoxymethylmorpholino, 4-methyl-3-fluoromethyl-1-piperazinyl,4-methyl-3-hydroxymethyl-1-piperazinyl,4-methyl-3-methoxymethyl-1-piperazinyl, 4-hydroxypiperidino,4-dimethylaminopiperidino, 1,8-diaza-4-oxabicyclo[4.4.0]deca-8-yl,4-oxopiperidino, and the like.

Among the cyclic amino group (Z), the groups ##STR8## contain anasymmetric carbon and hence, the compounds (I) containing these cyclicamino groups include optical isomers. Thus, the compounds of thisinvention include also these optical isomers and mixtures thereof.

The compounds of the present invention include a pharmaceuticallyacceptable salt of the compound of the formula (I). Preferredpharmaceutically acceptable salt of the compound (I) of the presentinvention are metallic salts such as sodium salt, potassium salt andcalcium salt, an ammonium salt and basic amino acid salts such as saltswith lysine and arginine at the carboxyl group; and where Z is, ##STR9##in which R² and R³ are as defined above, or 4-di(loweralkyl)aminopiperidino, or 1,8-diaza-4-oxabicyclo-[4.4.0]deca-8-yl##STR10## addition salts of inorganic acids such as hydrochloric acidand sulfuric acid, and of organic acids such as maleic acid, fumaricacid, tartaric acid, methanesulfonic acid and p-toluenesulfonic acid arealso included.

The compounds of the present invention (I) or a salt thereof can beprepared by, for example, reacting an intermediate compound (II) with acyclic amine (ZH) or an acid addition salt thereof in a polar organicsolvent such as dimethyl sulfoxide or N,N-dimethylformamide in thepresence of an acid scavenger, optionally followed by hydrolysis of theproduct as shown in the following process (A): ##STR11## wherein R ishydrogen atom, a lower alkyl, di(lower acyloxy)boryl, or difluoroboryl,and Z is as defined above,

That is, the compounds (I) of the present invention can directly beprepared by reacting the compound (II) wherein R is hydrogen atom with acyclic amine (ZH) or an acid addition salt thereof, or alternatively byreacting the compound (II) wherein R is a lower alkyl, di(loweracyloxy)-boryl [-B(lower acyloxy)₂ ] or difluoroboryl (--BF₂) with acyclic amine (ZH) or an acid addition salt thereof to produce an ester,followed by hydrolysis of said ester.

The acid scavenger includes a tertiary amine such as triethylamine or aninorganic base such as sodium carbonate or potassium carbonate. Anexcess amount of the above cyclic amine (ZH) can also be employed as theacid scavenger. When the tertiary amine or the inorganic base isemployed as the acid scavenger, the reaction is usually carried out insuch a way that one mole of the compound (II) is reacted with 1 to 1.5moles of the cyclic amine (ZH) or the acid addition salt thereofemploying 2 to 6 moles of the acid scavenger. When the cyclic amine (ZH)is used as the acid scavenger, one mole of the compound (II) is reactedwith an excess amount, usually 3 to 7 moles, of the cyclic amine (ZH).

The reaction temperature in the reaction of the compound (II) and thecyclic amine (ZH) or an acid addition salt thereof may vary inaccordance with the kinds of these compounds but is usually in the rangeof from room temperature to 150° C. When there is used as the compound,(II) a compound in which R is di(lower acyloxy)boryl [referred to as"compound (II-1)"], a compound in which R is difluoroboryl [referred toas "compound (II-2)"], or a compound in which R is hydrogen atom[referred to as "compound (II-3)"], the reaction proceeds rapidly undermilder conditions than the reaction using a compound in which R is alower alkyl [referred to as "compound (II-4)"]. That is, the reactionusing the former compound (II-1), (II-2) or (II-3) is usually carriedout for about 1 to 30 hours, but on the other hand, the reaction usingthe latter compound (II-4) is usually carried out for 10 to 250 hours.

The hydrolysis of the reaction product of the compound (II-1)with thecyclic amine (ZH) or an acid addition salt thereof is usually carriedout under an acidic condition, preferably hydrochloric acid acidiccondition, in a mixture of a water-soluble organic solvent (e.g.acetone, methanol, ethanol, etc.) and water at a temperature of fromroom temperature to the boiling temperature of the solvent, for 1 to 10hours.

The hydrolysis of the reaction product of the compound (II-2) or thecompound (II-4) with the cyclic amine (ZH) or an acid addition saltthereof is usually carried out under an alkaline condition in a mixtureOf a water-soluble organic solvent (e.g. acetone, methanol, ethanol,etc.) and water at a temperature of from room temperature to boilingtemperature of the solvent, for 1 to 12 hours.

The compounds of the formula (I) wherein Z is 2-hydroxymethylmorpholino[referred to as "compound (I')"] of the present invention can also beprepared by the following process (B). ##STR12## wherein R is as definedabove and R⁵ is a lower alkyl, phenyl or a lower alkyl-substitutedphenyl.

That is, the compound (II) is reacted with a 2-acyloxymethylmorpholineor an acid addition salt thereof in the same manner as in the aboveprocess (A) and hydrolyzing the reaction product in the conventionalmanner to give the compound (I') of the present invention.

The compounds (I) of the present invention thus prepared by the aboveprocesses, or an acid addition salt thereof, can be isolated andpurified by the conventional procedure, for example, silica-gel columnchromatography or recrystallization. The compounds (I) of the presentinvention can also be converted into the pharmaceutically acceptablesalts thereof by the conventional procedure.

The intermediate compounds (II) used in the above processes forpreparing the compound (I) of the present invention are prepared, forexample, by a process as shown in the following reaction scheme:##STR13## wherein R³ is as defined above.

That is, first the known compound (III) (see European patent publicationNo. 286089) is reacted with 1,3-dichloroacetone in an organic solventsuch as chloroform, ethyl acetate, methylene chloride or a lower alcoholto produce 3-chloro-2-oxopropylN-(2,3,4-trifluorophenyl)-dithiocarbamate (IV). The compound (IV) isthen reacted with an inorganic acid such as hydrogen chloride orsulfuric acid in a lower alcohol such as ethanol or ethyl acetate togive 4-chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-1,3-thiazolethione(V). The compound (V) is then reacted with methylamine in an organicsolvent such as N,N-dimethylformamide or acetonitrile to give1H,4H-thiazolo[3,4-a]-quinoxaline-1-thione derivative (VI). The compound(VI) is then reacted with a lower alkyl iodide in a polar solvent suchas N,N-dimethylformamide, acetonitrile or ethanol to give a 1-(loweralkyl)thioquinoxalino[1,2-c]thiazolium iodide (VII). Then the compound(VII) is reacted with a di(lower alkyl) malonate sodium, which isprepared from di(lower alkyl) malonate and sodium hydride, in an organicsolvent such as tetrahydrofuran or dioxane to give di(lower alkyl)(1H,4H-thiazolo[3,4-a]quinoxalin-1-ylidene)malonate (VIII).

Alternatively, the compound (VIII) can also be prepared by reacting thecompound (VI) with phosgene or trichloromethyl chloroformate in an inertsolvent such as toluene or benzene and then reacting the obtainedproduct with a di(lower alkyl) malonate in a solvent such asacetonitrile in the presence of a tertiary amine such as triethylamine.

The compound (VIII) is subsequently heated with a condensing agent suchas polyphosphoric acid or polyphosphoric acid ethyl ester to cyclize thecompound (VIII) to produce the compound (II) wherein R is a lower alkyl,i.e. the compound (II-4).

The compound (II-4) is reacted with a tri(lower acyloxy)borane in alower alkylcarboxylic acid anhydride to give the compound (II) wherein Ris a di(lower acyloxy)-boryl, i.e. the compound (II-1).

The compound (II) wherein R is hydrogen atom, i.e. the compound (II-3)is prepared by hydrolyzing the compound (II-1) under acidic conditions,preferably hydrochloric acid acidic condition, or alternatively byheating the compound (II-4) in conc. sulfuric acid at 60° to 100° C.

The compound (II) wherein R is difluoroboryl, i.e. the compound (II-2),can easily be prepared by reacting the compound (VIII) with borontrifluoride, boron trifluoride complex such as boron trifluorideetherate, hydrofluoroboric acid, or hydrofluoroboric acid salt (e.g.ammonium fluoroborate) in an acid anhydride such as acetic anhydride.

Among the cyclic amines (ZH), the compounds of the formula: ##STR14##(wherein R¹, R² and R³ are as defined above) and the compound of theformula: ##STR15## or acid addition salts of them are prepared by thefollowing processes.

That is, the compound (IX) or an acid addition salt thereof can beprepared by hydrogenolysis of the corresponding 4-benzylmorpholinederivative (XII) or an acid addition salt thereof in a lower alcohol oracetic acid or a lower alcohol containing an organic or inorganic acid(e.g. acetic acid, hydrochloric acid, etc.) in the presence of apalladium catalyst as shown in the following reaction scheme: ##STR16##wherein R¹ is as defined above.

Among the compounds (XII), the compounds of the formula (XII) wherein R¹is hydrogen atom, a halogen atom or hydroxy [referred to as "compound(XII-1)"] or an acid addition salt thereof can be prepared by reactingan epoxy compound (XIII-1) and N-benzylethanolamine and subjecting todehydrocondensation reaction in conc. sulfuric acid as shown in thefollowing reaction scheme (cf. Synthetic Communication, Vol. 10, pages59-73, 1980). ##STR17## wherein R⁶ is hydrogen atom, a halogen atom orhydroxy.

The 4-benzyl-2-hydroxymethylmorpholine [the compound (XII 1) wherein R⁶is hydroxy] can also be prepared by hydrolysis of4-benzyl-2-chloromethylmorpholine [the compound (XII-1) wherein R⁶ ischlorine] (cf. Synthetic Communication, Vol. 10, pages 59-73, 1980).

The 4-benzylmorpholine derivatives (XII) wherein R¹ is a lower alkyloxy[referred to as compound (XII-2)] can be prepared by reacting a4-benzyl-2-halogenomethylmorpholine compound (XII-1) wherein R⁶ is ahalogen atom] or a known4-benzyl-2-(p-toluenesulfonyloxymethyl)morpholine with a loweralcoholate, or alternatively from an epoxy compound (XIII-2) as shown inthe following reaction scheme. ##STR18## wherein R³ is as defined above.

That is, the epoxy compound (XIII-2) is reacted withN-benzylethanolamine and then reacting the reaction product with a loweralkylsulfonyl chloride (e.g. methanesulfonyl chloride, etc.) or anarylsulfonyl chloride (e.g. p-toluenesulfonyl chloride, etc.) in anaprotic organic solvent in the presence of a phase transfer catalyst(e.g. tris(3,6-dioxaheptyl)amine, 18-crown-6, etc.) and an inorganicbase (e.g. potassium hydroxide, sodium hydroxide, etc.) to give thecompound (XII-2).

The 2-acyloxymethylmorpholine of the formula: ##STR19## wherein R⁵ is asdefined above, which is used in the above process (B) for preparing thecompound (I'), can also be prepared by hydrogenolysis of thecorresponding 4-benzyl compound as mentioned hereinabove, said 4-benzylcompound being prepared by acylating 4-benzyl-2-hydroxymethylmorpholinewith an acid chloride or an acid anhydride, or alternatively by reacting4-benzyl-2-(p-toluenesulfonyloxymethyl)morpholine with a carboxylic acidin the presence of an inorganic base (e.g. potassium carbonate, sodiumcarbonate, etc.) in a polar organic solvent.

Besides, the compound (X) of the formula: ##STR20## wherein R² and R³are as defined above, can also be prepared by hydrogenolysis of thecorresponding N-benzyl compound (XIV) in acetic acid or an organicsolvent containing an organic or inorganic acid (e.g. acetic acid,hydrochloric acid, etc.) in the presence of a palladium catalyst,followed by treating the resulting acid addition salt of the compound(X) with an alkali as shown in the following reaction scheme: ##STR21##wherein R² and R³ are as defined above.

The above N benzyl compound (XIV) can be prepared in various manner inaccordance with the kinds of the substituents as shown in the followingreaction scheme: ##STR22## wherein R³ is as defined above, X¹ ischlorine atom or bromine atom, and X² is fluorine atom or iodine atom.That is, ethyl piperazine-2-carboxylate (cf. Helv. Chim. Acta, Vol. 45,page 2383, 1962) or an acid addition salt thereof is reacted with aboutan equimolar amount of benzyl bromide in an organic solvent (e.g.methylene chloride, ethanol, ethyl acetate, etc.) in the presence of anorganic basic compound (e.g. triethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, etc.) to give ethyl4-benzylpiperazine-2-carboxylate (XV). The compound (XV) is reacted witha lower alkyl halide to give the compound (XVI). The compound (XVI)wherein R³ is methyl can also be prepared by reacting the compound (XV)with formaline and formic acid.

The compound (XVI) obtained above is then treated with a reducing agent(e.g. lithium aluminum hydride, etc.) to give the compound (XIV) whereinR² is hydroxy [referred to as "compound (XIV-1)"]. The compound (XIV-1)is then reacted with a halogenating agent (e.g. thionyl chloride,thionyl bromide, etc.) in a solvent (e.g. carbon tetra chloride,chloroform, etc.) to give the compound (XIV) wherein R² is chlorine orbromine atom [referred to as "compound (XIV-2)"]. The compound (XIV-2)is reacted with a lower alcoholate to give the compound (XIV) wherein R²is a lower alkyloxy [referred to as "compound (XIV-3)"]. The compound(XIV) wherein R² is fluorine atom or iodine atom [referred to as"compound (XIV-4)"] can be prepared by reacting the compound (XIV-2)with a hydrofluoric acid salt (e.g. sodium fluoride, etc.) or ahydroiodic acid salt (e.g. sodium iodide, etc.).

Moreover, the compound of the formula (XI): ##STR23## which is one ofthe cyclic amines (ZH) can be prepared by the process as shown in thefollowing reaction scheme: ##STR24## wherein R³ is as defined above, andBoc means tert-butyloxycarbonyl.

That is, N-tert-butloxycarbonylserine (XVII) is condensed withbenzylamine in methylene chloride in the presence of a condensing agentsuch as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride togive the benzylamide compound (XVIII). The compound (XVIII) is reactedwith bromoacetic acid in tetrahydrofuran in the presence of potassiumtert-butoxide to give the compound (XIX). The compound (XIX) is thenreacted with a lower alkyl halide in the presence of an inorganic basicsubstance (e.g. potassium carbonate, sodium carbonate, etc.) in a polarorganic solvent (e.g. N,N-dimethylformamide, dimethylsulfoxide, etc.) togive the compound (XX) The compound (XX) is treated in 4N hydrogenchloride solution in dioxane to remove the N-tert-butyloxycarbonylprotecting group, followed by cyclizing the resulting compound bytreating with a basic substance (e.g. potassium carbonate, sodiumcarbonate, etc.) in a polar organic solvent (e.g. N,N-dimethylformamide,methanol, etc.) to give the compound (XXI). The compound (XXI) is thentreated with a reducing agent (e.g. lithium aluminum hydride, sodiumbis(2-methoxyethoxy)aluminum hydride, etc.) in an inert organic solvent(e.g. toluene, ether, etc.) to give the compound (XXII). The compound(XXII) is then reacted with 1,2-dibormoethane in the presence of aninorganic basic substance (e.g. potassium carbonate, sodium carbonate,etc.) in a polar organic solvent (e.g. N,N-dimethylformamide,dimethylsulfoxide, etc.) to give the compound (XXIII). Finally, thecompound (XXIII) is subjected to hydrogenolysis in the presence of apalladium catalyst to give the compound (XI). The compound (XI) caneasily be converted into its acid addition salt by treating the compound(XI) with an organic or inorganic acid (e.g. acetic acid, hydrochloricacid, etc.).

The compounds (I) of this invention include the optical isomers asmentioned above, and these optical isomers can also be prepared by theprocesses (A) and (B) by using optically active cyclic amine (ZH) or aderivative thereof.

The optically active cyclic amines can be prepared by resolution of theracemic mixture or alternatively by using an optically activeintermediate. The optically active intermediate, for example, opticallyactive 4-benzyl-2-lower alkyloxymethylmorpholine can be prepared byresolution of racemic mixture of known4-benzyl-2-(p-toluenesulfonyloxymethyl)morpholine (cf. Journal ofMedicinal Chemistry, Vol. 19, page 1074, 1976), followed by reacting theresultant with a lower alcoholate. Besides, an optically active4-benzyl-2-acyloxymethylmorpholine can be prepared by reacting theabove-mentioned resolved4-benzyl-2-(p-toluenesulfonyloxymethyl)morpholine with a carboxylicacid.

The compounds (I) of the present invention and pharmaceuticallyacceptable salts thereof show excellent antibacterial activities with alow toxicity as shown hereinbelow and are useful as an antibacterialagent.

When the compounds (I) of the present invention and pharmaceuticallyacceptable salts thereof are used for an antibacterial agent, they areadministered to human by oral route or parenterally such as byinjection. The dosage form for oral administration includes solidpreparations such as tablets, granules, powders, fine granules and hardcapsules as well as liquid preparations such as syrups and softcapsules. The pharmaceutical preparations can be prepared by theconventional procedure. Tablets, granuls, powders and fine granules areprepared by mixing the compound (I) of the present invention or apharmaceutically acceptable salt thereof with conventionalpharmaceutically acceptable nontoxic carriers such as lactose, starch,crystalline cellulose, magnesium stearate, hydroxypropyl cellulose,talc, and the like. Hard capsuls are prepared by packing the above finegranules or powders into capsules. Syrups are prepared by dissolving orsuspending the compound (I) of the present invention or apharmaceutically acceptable salt thereof in an aqueous solutioncontaining white sugar, carboxymethyl cellulose and the like. Softcapsules are prepared by dissolving or suspending the compound (I) ofthe present invention or a pharmaceutically acceptable salt thereof infatty diluents such as vegetable oils, oil emulsions and glycols andpacking the solution or suspension into soft capsules.

Injections are prepared by dissolving or suspending the compound (I) ofthe present invention or a pharmaceutically acceptable salt thereof inphysiological saline or in fatty diluents such as vegetable oils, oilemulsions and glycols and aseptically packing the solution or emulsionin ampoules or vials.

The dose of the compound (I) of the present invention, though it mayvary depending on an age or a body weight of patients or severity ofdiseases, is generally in the range of from 0.5 to 30 mg/kg of bodyweight/day, preferably from 2 to 20 mg/kg of body weight/day [as thecompound (I)], which may be administered once a day or may be dividedinto 2 to 4 times per day.

The compounds (I) of the present invention and pharmaceuticallyacceptable salts thereof have a wider antibacterial spectrum and potentantibacterial activities as shown in the following Experiment 1. Thecompounds (I) of the present invention and pharmaceutically acceptablesalts thereof show particulally strong antibacterial activities againstGram positive bacteria and also show strong antibacterial activitiesagainst clinically isolated bacteria as demonstrated in the followingExperiment 2. Further, tests employing experimental animals prove thatthe compounds (I) of the present invention and pharmaceuticallyacceptable salts thereof, e.g. the compounds prepared in Examples 1, 2,3, 7, 11 and 20, showed excellent protective effects against infectionas seen in the following Experiments 3 and 4 and had low toxicity asdemonstrated in the following Experiments 5 to 8. Consequently, it isclear that the compounds (I) of the present invention andpharmaceutically acceptable salts thereof are useful as an excellentagent for the prophylaxis and treatment of various infectious diseases,particularly infectious deseases induced by Gram positive bacteria.

The antibacterial activities of the compounds (I) of the presentinvention and pharmaceutically acceptable salts thereof were tested inthe following Experiments. The compounds used in these Experimentsinclude compounds having an asymmetric carbon, but unless theconfiguration of the asymmeric carbon is specified, these compounds meanracemic compounds.

EXPERIMENT 1 Antibacterial Activities (Minimum Inhibitory Concentration:MIC) 1. Test Compounds

The following compounds of the present invention were tested forantibacterial activities. The known compounds (X) and (Y) as mentionedabove were also tested as reference.

Compound (A):9,1-(Methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 1]

Compound (B):9,1-(Methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 2]

Compound (C):9,1-(Methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 3]

Compound (D):9,1-(Methylimino)methano-7-fluoro-8-(2-chloromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 4]

Compound (E):9,1-(Methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylic acid [compound of Example 5]

Compound (F):9,1-(Methylimino)methano-7-fluoro-8-[(6R)-1,8-diaza-4-oxabicyclo[4.4.0]deca-8-yl]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 7]

Compound (G):9,1-(Methylimino)methano-7-fluoro-8-(4-oxopiperidino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 8]

Compound (H):9,1-(Methylimino)methano-7-fluoro-8-(4-dimethylaminopiperidino)-5-oxo-5H-thaizolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 9]

Compound (I):9,1-(Methylimino)methano-7-fluoro-8-(3-hydroxymethyl-4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid hydrochloride [compound of Example 10]

Compound (J):9,1-(Methylimino)methano-7-fluoro-8-(3-methoxymethyl-4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid hydrochloride [compound of Example 11]

Compound (K):9,1-(Methylimino)methano-7-fluoro-8-(3-fluoromethyl-4-methyl-1piperazinyl) 5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acidhydrochloride [compound of Example 12]

Compound (L):9,1-(Methylimino)methano-7-fluoro-8-(4-hydroxypiperidino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 13]

Compound (M): 9,1-(Methylimino)methano-7-fluoro-8-(2S)-2-hydroxymethylmorpholino]-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 17]

Compound (N):9,1-(Methylimino)methano-7-fluoro-8-(2R)-2-hydroxymethylmorpholino]-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-caboxylicacid [compound of Example 18]

Compound (O):9,1-(Methylimino)methano-7-fluoro-8-(2S)-2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 21]

Compound (P):9,1-(Methylimino)methano-7-fluoro-8-(2R)-2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 22]

Compound (Q):9,1-(Methylimino)methano-7-fluoro-8-(2-ethoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid (compound of Example 24)

Compound (X):9-Fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylicacid (reference compound disclosed in U.S. Pat. No. 4,382,892)

Compound (Y):9,1-Epoxymethano-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid hydrochloride (reference compound disclosed in European PatentPublication No. 286089)

2. Test Method

The compounds of the present invention (A, C, D, F, and L) and the knowncompound (X) as reference were each dissolved in 0.1N aqueous sodiumhydroxide to prepare a solution of 5000 μg/ml in concentration. Thecompounds of the present invention (B, E, G, H, M, N, O, P and Q) wereeach dissolved in dimethylsulfoxide to prepare a solution of 5000 μg/mlin concentration. The compounds of the present invention (I, J and K)and the known compound (Y) were each dissolved in sterilized distilledwater to prepare a solution of 5000 μg/ml in concentration. Eachsolution was diluted with sterilized distilled water to prepare astandard solution with a concentration of each test compound: 1000μg/ml. The test was carried out by a method as appointed by JapanSociety of Chemotherapy [cf. Chemotherapy, 29, 76-79 (1981), TOKYO].

As to Streptococcus pneumoniae and Streptococcus pyogenes, Brain heartinfusion broth (manufactured by DIFCO) was used as the medium for thepreculture thereof, and a heart infusion agar medium containing 5%defibrinated horse blood (manufactured by Nissui Seiyaku K.K., Japan)was used as the medium for the measurement of minimum inhibitoryconcentration (MIC). As to other microorganisms, a sensitivity testbroth (manufactured by Nissui Seiyaku K.K.) was used as the medium forthe preculture thereof, and a sensitivity test agar medium (manufacturedby Nissui Seiyaku K.K.) was used as the medium for the measurement ofMIC.

3. Results

The test results are shown in Tables 1-1 to 1-4.

                                      TABLE 1                                     __________________________________________________________________________                    Min. inhib. concentr. (MIC: μg/ml)                                         Compounds of the present invention                            Microorganisms                                                                            Gram                                                                              A   B   C   D   E   F   G   H   I   J                         __________________________________________________________________________    Staphylococcus                                                                            +   0.013                                                                             0.013                                                                             0.013                                                                             0.013                                                                             0.025                                                                             0.025                                                                             0.013                                                                             0.10                                                                              0.20                                                                              0.05                      aureus FDA 209P JC-1                                                          Staphylococcus                                                                            +   ≦0.006                                                                     0.013                                                                             ≦0.006                                                                     ≦0.006                                                                     0.013                                                                             0.013                                                                             ≦0.006                                                                     0.10                                                                              0.20                                                                              0.10                      aureus IID 803                                                                Staphylococcus                                                                            +   0.013                                                                             0.025                                                                             0.013                                                                             0.025                                                                             0.025                                                                             0.05                                                                              0.013                                                                             0.05                                                                              0.20                                                                              0.10                      aureus Terajima                                                               (IID 670)                                                                     Staphylococcus                                                                            +   0.013                                                                             0.025                                                                             0.013                                                                             0.013                                                                             0.013                                                                             0.025                                                                             ≦0.006                                                                     0.10                                                                              0.39                                                                              0.10                      aureus MS-353                                                                 Staphylococcus                                                                            +   0.013                                                                             0.013                                                                             0.013                                                                             0.013                                                                             ≦0.006                                                                     0.025                                                                             ≦0.006                                                                     0.05                                                                              0.20                                                                              0.05                      aureus Cowan I                                                                (IID 975)                                                                     Staphylococcus                                                                            +   0.013                                                                             ≦0.006                                                                     0.013                                                                             0.013                                                                             0.013                                                                             0.025                                                                             ≦0.006                                                                     0.05                                                                              0.10                                                                              0.10                      aureus ATCC 9144                                                              Staphylococcus                                                                            +   ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.013                                                                             ≦0.006                                                                     0.05                                                                              0.10                                                                              0.05                      aureus  FDA 243                                                               Staphylococcus                                                                            +   0.05                                                                              0.05                                                                              0.025                                                                             0.025                                                                             0.05                                                                              0.05                                                                              0.013                                                                             0.20                                                                              0.20                                                                              0.20                      epidermidis                                                                   IAM 1296                                                                      Streptococcus                                                                             +   0.025                                                                             0.025                                                                             0.025                                                                             0.025                                                                             0.05                                                                              0.05                                                                              0.013                                                                             0.05                                                                              0.05                                                                              0.10                      pyogenes Su                                                                   Streptococcus                                                                             +   0.025                                                                             0.025                                                                             0.05                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.025                                                                             0.05                                                                              0.05                                                                              0.10                      pyogenes Cook                                                                 Streptococcus                                                                             +   0.025                                                                             0.05                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.025                                                                             0.05                                                                              0.10                                                                              0.10                      pyogenes Sv                                                                   Streptococcus                                                                             +   0.013                                                                             0.025                                                                             0.025                                                                             0.05                                                                              0.05                                                                              0.05                                                                              0.025                                                                             0.05                                                                              0.10                                                                              0.05                      pneumoniae IID 552                                                            Streptococcus                                                                             +   0.05                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.025                                                                             0.05                                                                              0.05                                                                              0.10                      pneumoniae IID 554                                                            Bacillus subtilis                                                                         +   ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.013                                                                             ≦0.006                                                                     0.05                                                                              0.10                                                                              0.05                      ATCC 6633                                                                     Bacillus cereus                                                                           +   0.013                                                                             0.025                                                                             0.013                                                                             0.025                                                                             0.025                                                                             0.025                                                                             0.013                                                                             0.05                                                                              0.20                                                                              0.10                      IAM 1029                                                                      Micrococcus luteus                                                                        +   0.10                                                                              0.10                                                                              0.10                                                                              0.05                                                                              0.10                                                                              0.20                                                                              0.05                                                                              0.39                                                                              0.39                                                                              0.39                      ATCC 9341                                                                     Escherichia coli                                                                          -   0.10                                                                              0.10                                                                              0.20                                                                              0.20                                                                              0.20                                                                              0.39                                                                              0.10                                                                              0.20                                                                              0.20                                                                              0.39                      NIHJ JC-2                                                                     Klebsiella  -   ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.025                                                                             0.025                                                                             0.013                                                                             ≦0.006                                                                     0.025                                                                             0.025                                                                             0.05                      pneumoniae PCI-602                                                            Pseudomonas aeruginosa                                                                    -   0.39                                                                              0.39                                                                              0.39                                                                              0.39                                                                              1.56                                                                              0.78                                                                              0.39                                                                              0.78                                                                              0.78                                                                              1.56                      NCTC 10490                                                                    Proteus mirabilis                                                                         -   0.20                                                                              0.39                                                                              0.20                                                                              0.39                                                                              0.78                                                                              0.78                                                                              0.20                                                                              0.78                                                                              0.78                                                                              1.56                      IFO 3849                                                                      Enterobacter cloacae                                                                      -   0.20                                                                              0.20                                                                              0.20                                                                              0.39                                                                              0.78                                                                              0.78                                                                              0.20                                                                              0.39                                                                              0.20                                                                              0.39                      963                                                                           Acinetobacter                                                                             -   ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.013                                                                             0.013                                                                             ≦0.006                                                                     0.10                                                                              0.10                                                                              0.10                      calcoaceticus Ac 54                                                           __________________________________________________________________________                        Min. inhib. concentr. (MIC: μg/ml)                                                             Compds. of                                                Compounds of the present invention                                                                the invention                                                                         Known comp.                   Microorganisms  Gram                                                                              K   L   M   N   O   P   Q   X   Y                         __________________________________________________________________________    Staphylococcus  +   0.05                                                                              0.013                                                                             0.013                                                                             0.013                                                                             0.025                                                                             0.05                                                                              0.10                                                                              0.39                                                                              0.20                      aureus FDA 209P JC-1                                                          Staphylococcus  +   0.05                                                                              ≦0.006                                                                     0.013                                                                             0.013                                                                             0.013                                                                             0.025                                                                             0.05                                                                              0.39                                                                              0.20                      aureus IID 803                                                                Staphylococcus  +   0.05                                                                              0.013                                                                             0.025                                                                             0.025                                                                             0.025                                                                             0.05                                                                              0.10                                                                              0.39                                                                              0.10                      aureus Terajima                                                               (IID 670)                                                                     Staphylococcus  +   0.05                                                                              0.013                                                                             0.025                                                                             0.025                                                                             0.013                                                                             0.025                                                                             0.10                                                                              0.78                                                                              0.10                      aureus MS-353                                                                 Staphylococcus  +   0.05                                                                              ≦0.006                                                                     0.013                                                                             0.013                                                                             ≦0.006                                                                     ≦0.006                                                                     0.05                                                                              0.39                                                                              0.10                      aureus Cowan I                                                                (IID 975)                                                                     Staphylococcus  +   0.05                                                                              ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.025                                                                             0.013                                                                             0.025                                                                             0.39                                                                              0.05                      aureus ATCC 9144                                                              Staphylococcus  +   0.05                                                                              ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.05                                                                              0.39                                                                              0.05                      aureus FDA 243                                                                Staphylococcus  +   0.10                                                                              0.013                                                                             0.05                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.10                                                                              0.78                                                                              0.39                      epidermidis                                                                   IAM 1296                                                                      Streptococcus   +   0.05                                                                              0.025                                                                             0.025                                                                             0.025                                                                             0.05                                                                              0.05                                                                              0.20                                                                              0.78                                                                              0.10                      pyogenes Su                                                                   Streptococcus   +   0.10                                                                              0.025                                                                             0.05                                                                              0.025                                                                             0.05                                                                              0.05                                                                              0.20                                                                              0.78                                                                              0.10                      pyogenes Cook                                                                 Streptococcus   +   0.10                                                                              0.025                                                                             0.05                                                                              0.05                                                                              0.05                                                                              0.10                                                                              0.39                                                                              0.78                                                                              0.20                      pyogenes Sv                                                                   Streptococcus   +   0.05                                                                              0.013                                                                             0.05                                                                              0.025                                                                             0.05                                                                              0.05                                                                              0.39                                                                              0.78                                                                              0.10                      pneumoniae IID 552                                                            Streptococcus   +   0.10                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.05                                                                              0.10                                                                              0.39                                                                              0.78                                                                              0.20                      pneumoniae IID 554                                                            Bacillus subtilis                                                                             +   0.013                                                                             ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.013                                                                             ≦0.006                                                                     0.05                                                                              0.10                                                                              0.10                      ATCC 6633                                                                     Bacillus cereus +   0.05                                                                              0.013                                                                             0.025                                                                             0.025                                                                             0.025                                                                             0.025                                                                             0.10                                                                              0.39                                                                              0.39                      IAM 1029                                                                      Micrococcus luteus                                                                            +   0.39                                                                              0.10                                                                              0.20                                                                              0.10                                                                              0.10                                                                              0.20                                                                              0.39                                                                              3.13                                                                              1.56                      ATCC 9341                                                                     Escherichia coli                                                                              -   0.20                                                                              0.10                                                                              0.10                                                                              0.20                                                                              0.20                                                                              0.20                                                                              0.78                                                                              0.10                                                                              0.10                      NIHJ JC-2                                                                     Klebsiella      -   0.013                                                                             ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.013                                                                             0.025                                                                             0.20                                                                              0.05                                                                              0.025                     pneumoniae PCI-602                                                            Pseudomonas aeruginosa                                                                        -   0.78                                                                              0.39                                                                              0.39                                                                              0.39                                                                              0.78                                                                              1.56                                                                              1.56                                                                              1.56                                                                              0.78                      NCTC 10490                                                                    Proteus mirabilis                                                                             -   0.39                                                                              0.20                                                                              0.39                                                                              0.39                                                                              0.78                                                                              0.78                                                                              1.56                                                                              0.39                                                                              0.20                      IFO 3849                                                                      Enterobacter cloacae                                                                          -   0.20                                                                              0.20                                                                              0.20                                                                              0.39                                                                              0.78                                                                              1.56                                                                              1.56                                                                              0.20                                                                              0.10                      963                                                                           Acinetobacter   -   0.025                                                                             ≦0.006                                                                     ≦0.006                                                                     ≦0.006                                                                     0.013                                                                             0.013                                                                             0.05                                                                              0.39                                                                              0.20                      calcoaceticus Ac 54                                                           __________________________________________________________________________

Experiment 2 In Vitro Antibacterial Activity Against ClinicalIsolates 1. Test Compounds

The same as in Experiment 1 [that is, the compounds (A) to (Q) of thepresent invention and known compounds (X) and (Y)].

2. Method

The compounds (A), (C), (D), (F) and (L) of the present invention andthe known compound (X) were dissolved in 0.1N aqueous sodium hydroxide,the compounds (B), (E), (G), (H), (M), (N), (O), (P), and (Q) of thepresent invention in dimethylsulfoxide, and the compounds (I), (J) and(K) of the present invention and the known compound (Y) in sterilizeddistilled water, to prepare a solution of 5000 μg/ml in concentration,respectively. The above solutions were then diluted with sterilizeddistilled water to prepare a standard solution with a concentration ofthe test compound: 1000 μg/ml each. The test was carried out by a methodappointed by Japan Society of Chemotherapy (Chemotherapy, 29, 76-79(1981), TOKYO) to measure minimum inhibitory concentration (MIC) against25 strains of clinically isolated Staphylococcus aureus including 16methicillin resistant strains having MIC more than 6.25 μg/ml againstmethicillin, 25 strains of clinically isolated Staphylococcusepidermidis, 25 strains of clinically isolated Enterococcus faecalis,and 25 strains of clinically isolated Enterococcus faecium, from whichthere were calculated a range of MIC (MIC_(range)) of the test compoundagainst these resistant strains, a minimum concentration for inhibitingthe growth of the strains by 50% (MIC₅₀) and a minimum concentration forinhibiting the growth of the strains by 90% (MIC₉₀).

For the preculture of each microorganism, there was used as the medium asensitivity test broth (manufactured by Nissui Seiyaku K.K., Japan), andfor the measurement of MIC, there was used a sensitivity test agarmedium (manufactured by Nissui Seiyaku K.K.).

The clinically isolates used above were isolated from November 1988 toJune 1989 and were obtained from Research Section, Tokyo ClinicalResearch Center.

3. Results

The test results are shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Test microorganisms                                                           Staphylococcus aureus Staphylococcus epidermidis                              Test MIC.sub.range                                                                        MIC.sub.50                                                                         MIC.sub.90                                                                         MIC.sub.range                                                                        MIC.sub.50                                                                         MIC.sub.90                                  compds.                                                                            (μg/ml)                                                                           (μg/ml)                                                                         (μg/ml)                                                                         (μg/ml)                                                                           (μg/ml)                                                                         (μg/ml)                                  __________________________________________________________________________    (A)  ≦0.006-0.20                                                                   ≦0.006                                                                      0.20 ≦0.006-0.39                                                                   0.013                                                                              0.20                                        (B)  ≦0.006-0.78                                                                   0.013                                                                              0.78 ≦0.006-0.78                                                                   0.025                                                                              0.39                                        (C)  ≦0.006-0.20                                                                   0.013                                                                              0.20 ≦0.006-0.39                                                                   0.013                                                                              0.39                                        (D)  ≦0.006-0.20                                                                   0.013                                                                              0.20 ≦0.006-0.39                                                                   0.013                                                                              0.20                                        (E)  ≦0.006-0.78                                                                   0.013                                                                              0.78 ≦0.006-0.39                                                                   0.05 0.39                                        (F)   0.013-0.78                                                                          0.025                                                                              0.78  0.013-1.56                                                                          0.05 0.78                                        (G)  ≦0.006-0.39                                                                   ≦0.006                                                                      0.20 ≦0.006-0.20                                                                   0.013                                                                              0.20                                        (H)    0.05-3.13                                                                          0.10 3.13   0.05-3.13                                                                          0.05 3.13                                        (I)    0.10-12.5                                                                          0.20 6.25   0.05-3.13                                                                          0.10 3.13                                        (J)    0.05-6.25                                                                          0.10 3.13   0.05-6.25                                                                          0.10 3.13                                        (K)   0.025-1.56                                                                          0.05 1.56   0.05-1.56                                                                          0.05 0.78                                        (L)  ≦0.006-0.39                                                                   ≦0.006                                                                      0.39 ≦0.006-0.39                                                                   0.013                                                                              0.39                                        (M)  ≦0.006-0.78                                                                   0.013                                                                              0.78 ≦0.006-0.78                                                                   0.025                                                                              0.39                                        (N)  ≦0.006-0.78                                                                   0.013                                                                              0.78 ≦0.006-0.78                                                                   0.025                                                                              0.39                                        (O)  ≦0.006-0.78                                                                   0.013                                                                              0.78 ≦0.006-0.78                                                                   0.05 0.39                                        (P)  ≦0.006-0.78                                                                   0.013                                                                              0.78 ≦0.006-0.78                                                                   0.05 0.39                                        (Q)  ≦0.006-0.78                                                                   0.013                                                                              0.78 ≦0.006-0.78                                                                   0.025                                                                              0.39                                        (X)    0.39-50                                                                            1.56 25     0.20-50                                                                            0.78 25                                          (Y)    0.05-12.5                                                                          0.20 12.5  0.025-25                                                                            0.10 12.5                                        __________________________________________________________________________    Test microorganisms                                                           Enterococcus faecalis                                                                              Enterococcus faecium                                     Test MIC.sub.range                                                                       MIC.sub.50                                                                         MIC.sub.90                                                                         MIC.sub.range                                                                        MIC.sub.50                                                                         MIC.sub.90                                   compds.                                                                            (μg/ml)                                                                          (μg/ml)                                                                         (μg/ml)                                                                         (μg/ml)                                                                           (μg/ml)                                                                         (μg/ml)                                   __________________________________________________________________________    (A)  0.025-3.13                                                                          0.10 3.13 0.05-6.25                                                                            0.78 3.13                                         (B)  0.05-3.13                                                                           0.20 3.13 0.10-25                                                                              1.56 6.25                                         (C)  0.05-3.13                                                                           0.10 3.13 0.05-6.25                                                                            0.78 3.13                                         (D)  0.05-3.13                                                                           0.20 1.56 0.05-3.13                                                                            0.39 3.13                                         (E)  0.10-6.25                                                                           0.20 6.25 0.10-12.5                                                                            3.13 6.25                                         (F)  0.05-6.25                                                                           0.20 6.25 0.20-6.25                                                                            1.56 6.25                                         (G)  0.025-1.56                                                                          0.05 1.56 0.025-3.13                                                                           0.39 3.13                                         (H)  0.20-6.25                                                                           0.39 3.13 0.20-25                                                                              1.56 12.5                                         (I)  0.20-12.5                                                                           0.39 12.5 0.20- 25                                                                             3.13 12.5                                         (J)  0.20-12.5                                                                           0.39 12.5 0.39-25                                                                              3.13 12.5                                         (K)  0.20-6.25                                                                           0.39 6.25 0.20-12.5                                                                            1.56 12.5                                         (L)  0.05-1.56                                                                           0.05 1.56 0.05-6.25                                                                            0.39 3.13                                         (M)  0.05-3.13                                                                           0.20 3.13 0.10-25                                                                              1.56 3.13                                         (N)  0.05-3.13                                                                           0.20 3.13 0.10-25                                                                              1.56 6.25                                         (O)  0.05-3.13                                                                           0.20 3.13 0.10-12.5                                                                            3.13 6.25                                         (P)  0.10-6.25                                                                           0.20 6.25 0.20-12.5                                                                            3.13 12.5                                         (Q)  0.05-6.25                                                                           0.39 6.25 0.20-25                                                                              3.13 12.5                                         (X)  1.56-100                                                                            3.13 50     1.56->100                                                                          25   100                                          (Y)  0.20-6.25                                                                           0.39 6.25 0.39-12.5                                                                            3.13 6.25                                         __________________________________________________________________________

EXPERIMENT 3 Effect on Treatment of General Infectious Disease 1. TestCompounds

Compound (A):9,1-(Methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 1]

Compound (B):9,1-(Methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 2]

Compound (C):9,1-(Methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4carboxylicacid [compound of Example 3]

Compound (F):9,1-(Methylimino)methano-7-fluoro-8-[(6R)-1,8-diaza-4-oxabicyclo[4.4.0]deca-8-yl]-5-oxo-5H-thiazolo-[3,2-a]quinoline-4-carboxylicacid [compound of Example 7]

Compound (J): 9,1-(Methylimino)methano7-fluoro-8-(3-methoxymethyl-4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid hydrochloride [compound of Example 11]

Compound (X):9-Fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid (reference compound disclosed in U.S. Pat. No. 4,382,892)

Compound (Y):9,1-Epoxymethano-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid hydrochloride (reference compound disclosed in European PatentPublication No. 286089)

2. Test Microorganism

Staphylococcus aureus IID 803

3. Method

The test microorganism was subjected to standing culture in Brain heartinfusion broth (manufactured by DIFCO) at 37° C. for 16 to 18 hours. Theculture was then diluted with PBS (Dulbecco's phosphate buffered saline)to adjust the concentration of bacteria to 4×10⁷ -8×10⁷ CFU/ml. Themixture was mixed with an equivalent amount of 10% (w/v) Mucin (BACTOMUCIN BACTERIOLOGICAL, manufactured by Difco Co.) to prepare a bacterialsuspension. The thus prepared bacterial suspension (0.5 ml each) wasintraperitoneally inoculated to ddY male mice (5 weeks age, weighing24-27 g, 5 mice in each group), to infect the animals, by which systemicinfectious model was prepared.

One hour after the infection, the compound (A), (B), (C) or (F) of thepresent invention or the known compound (X) suspended in 1% (w/v)aqueous gum arabic or the compound (J) of the present invention or theknown compound (Y) dissolved in sterilized distilled water was orallyadiministered to mice.

The mice were daily observed for one week, and from the survival numberof mice after one week, the 50% effective dose (ED₅₀) was calculated byWeil method. This test was repeated several times and the average ofED₅₀ was calculated.

4. Results

The test results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Test compounds ED.sub.50 (mg/kg)                                              ______________________________________                                        Compound (A)   3.5                                                            Compound (B)   5.1                                                            Compound (C)   1.9                                                            Compound (F)   2.3                                                            Compound (J)   4.4                                                            Compound (X)   11.4                                                           Compound (Y)   10.8                                                           ______________________________________                                    

EXPERIMENT 4 Effect on Treatment of General Infectious Disease 1. TestCompound

Compound (E):9,1-(Methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid (compound of Example 20)

2. Test Microorganism

Staphylococcus aureus IID 803

3. Method

The test microorganism was subjected to standing culture in Brain heartinfusion broth (manufactured by DIFCO) at 37° C. for 16 to 18 hours. Theculture was then diluted with PBS (Dulbecco's phosphate buffered saline)to adjust the concentration of bacteria to 3×10⁷ CFU/ml. The mixture wasmixed with an equivalent amount of 10% (w/v) Mucin (BACTO MUCINBACTERIOLOGICAL, manufactured by Difco Co.) to prepare a bacterialsuspension. The thus prepared bacterial suspension (0.5 ml each) wasintraperitoneally inoculated to ddY male mice (5 weeks age, weighing22-29 g, 10 mice in each group), to infect the animals, by whichsystemic infectious model was prepared. One hour after the infection, asuspension of the test compound in 1% (w/v) aqueous gum arabic wasorally adiministered to mice.

The mice were daily observed for one week, and from the survival numberof mice after one week, the 50% effective dose (ED₅₀) was calculated byWeil method.

4. Results

The test results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        test compound  ED.sub.50 (mg/kg)                                              ______________________________________                                        Compound (E)   1.7                                                            ______________________________________                                    

EXPERIMENT 5 Acute Toxicity 1. Test Compounds

Compound (A):9,1-(Methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo5H-thiazolo[3,2-a]quinoline-4-carboxylic acid [compound of Example 1]

Compound (B):9,1-(Methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 2]

Compound (C):9,1-(Methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 3]

2. Method

The compound (A) or (B) of the present invention was suspended indistilled water to prepare a suspension in concentration of 200 mg/mland the compound (C) was suspended in distilled water to prepare asuspension in concentration of 100 mg/ml. The suspension was orallyadministered to ddY male mice (5 weeks age, weighing 19 to 24 g, 5 micein each group), which had been fasted for 18 hours, at a rate of 2000mg/kg body weight of the test compound. These mice were observed for thenumber dead for a week.

3. Results

After administration of the compound (A), (B) or (C) of the presentinvention at a rate of 2000 mg/kg body weight, no death of mice wasobserved.

EXPERIMENT 6 Acute Toxicity 1. Method

9,1-(Methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid (compound of Example 20) [the compound (E) of the presentinvention] was suspended in 1% aqueous gum arabic to prepare asuspension in concentration of 100 mg/ml. The suspension was orallyadministered to F344/DuCrj male and female rats (5 weeks age, weighing110 to 115 g in male, 91 to 95 g in female, 3 rats in each group), whichhad been fasted for 5 hours, at a rate of 1000 and 2000 mg/kg bodyweight of the test compound (E). These rats were observed for the numberdead for a week.

2. Results

After administration of the compound (E) of the present invention at arate of 1000 and 2000 mg/kg body weight, no death of rats was observed.

EXPERIMENT 7 Micronucleus Test 1. Method

9,1-(Methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid (compound of Example 3) [the compound (C) of the present invention]was suspended in sterilized distilled water. The suspension was orallyadministered to ICR male mice (8 weeks age, weighing 30 to 36 g, 3 micein each group) at a rate of 3000, 1000, 300 or 100 mg/kg body weight ofthe test compound (C). After 24 hours, these mice were killed and thebone marrow was collected and observed for the presence of micronuclei.

2. Results

The compound (C) of the present invention exhibited no nucleus inducingactivity.

EXPERIMENT 8 Micronucleus Test 1. Test Compounds

Compound (B):9,1-(Methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound of Example 15]

Compound (E):9,1-(Methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid (compound of Example 20)

2. Method

The compound (B) or (E) of the present invention was suspended in 1%aqueous gum arabic The suspension was orally administered to ICR malemice (7-8 weeks age, weighing 30 to 39 g, 5 mice in each group) at arate of 3000, 1000 or 300 mg/kg body weight of the test compound (B) or(E). After 24 hours or 48 hours, these mice were killed and the bonemarrow was collected and observed for the presence of micronuclei.

2. Results

The compounds (B) and (E) of the present invention exhibited no nucleusinducing activity.

EXAMPLES

The preparation of the compounds of the present invention is illustratedby means of the following Reference Examples and Examples, but shouldnot be construed to be limited thereto. In these examples, the compoundsare racemic mixture unless the configuration of asymmetric carbon isspecified.

REFERENCE EXAMPLE 1 Preparation of 3-chloro-2-oxopropylN-(2,3,4-trifluorophenyl)dithiocarbamate [compound (IV)]

1,3-Dichloroacetone (2.0 g) is added to methylene chloride (100 ml), andthereto is added triethylammoniumN-(2,3,4-trifluorophenyl)dithiocarbamate (cf. European PatentPublication 286089) (5.0 g) with stirring at 2° to 5° C. The mixture isstirred for additional 60 minutes and then washed with 3N hydrochloricacid and water in this order. The organic layer is dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent. The residue is crystallized from a mixture of hexane-ethylacetate-ether to give the title compound (4.2 g).

Mass spectrum (m/e): 313 (M+).

REFERENCE EXAMPLE 2 Preparation of4-chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione [compound(V)]

3-Chloro-2-oxopropyl N-(2,3,4-trifluorophenyl)-dithiocarbamate (4.0 g)is added to 30% hydrogen chloridemethanol solution (15 ml), and themixture is refluxed for 3 hours. The solvent is distilled off underreduced pressure, and cold water is added to the residue and the mixtureis extracted with chloroform. The extract is washed with salinesolution, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue is recrystallizedfrom cyclohexane to give the title compound (2.6 9) as pale yellowcrystals.

M.p. 127°-130° C.

NMR (CDCl₃) δ: 4.1 (1H, d, J=13Hz), 4.2 (1H, d, J=13Hz), 6.8 (1H, s),7.2 (2H, m).

IR (KBr) ν_(max) cm⁻¹ : 3072, 1516, 1504, 1314, 1260, 1102.

Elementary analysis for C₁₀ H₅ NS₂ F₃ Cl:

Calcd. (%): C,40.61; H,1.70; N,4.74

Found (%): C,40.59; H,1.80; N,4.71.

REFERENCE EXAMPLE 3 Preparation of5-methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]quinoxaline-1-thione[compound (VI)]

4-Chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione (2.5 g) isdissolved in acetonitrile (25 ml) and thereto is added 40% solution ofmethylamine in methanol (3.3 g), and the mixture is stirred at 50° C.for 16 hours. The reaction mixture is evaporated to dryness underreduced pressure, and water is added to the residue and the mixture isextracted with chloroform. The extract is washed with saline solution,dried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue is recrystallized fromcyclohexane-ethyl acetate to give the title compound (2.0 g) as yellowcrystals.

M.p. 165°-167° C.

NMR (CDCl₃) δ: 3.0 (3H, d, J=2.5Hz), 4.0 (2H, d, J=1Hz), 6.4 (1H, t,J=1Hz), 6.9 (1H, dt, J=8Hz, J=9Hz), 9.3 (1H, ddd, J=2.5Hz, J=5Hz,J=9.5Hz).

IR (KBr) ν_(max) cm⁻¹ : 1502, 1492, 1306, 1290, 1032.

Elementary analysis for C11H₈ N₂ S₂ F₂ :

Calcd. (%): C,48.87; H,2.98; N,10.36

Found (%): C,49.04; H,2.96; N,10.41.

REFERENCE EXAMPLE 4 Preparation of 5 methyl-6,7-difluoro-1-methylthio-4H-quinoxalino[1,2-c]thiazolium iodide [compound (VII) wherein R³ ismethyl]

5-Methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]quinoxaline-1-thione (0.4 g)and methyl iodide (0.4 g) are dissolved in N,N-dimethylformamide (3 ml),and the mixture is allowed to stand in dark room at room temperature for40 hours. The precipitates are collected by filtration and washed withacetonitrile and ether in this order to give the title compound (0.5 g)as yellow crystals.

NMR (DMSO-d₆) δ: 3.0 (3H, d, J=4Hz), 3.1 (3H, s), 4.4 (2H, s), 7.3 (1H,dt, J=8Hz, J=9.5Hz), 7.9 (1H, ddd, J=2Hz, J=5Hz, J=9.5Hz), 8.0 (1H, s).

REFERENCE EXAMPLE 5 Preparation of diethyl(5-methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]quinoxalin-1-ylidene)malonate[compound (VIII) in which R³ is ethyl]

Sodium hydride in oil (content, about 60 w/w %) (54 mg) is suspended intetrahydrofuran (3 ml) and thereto is added dropwise diethyl malonate(0.2 g) at 20° C., and the mixture is stirred for 20 minutes. To themixture is added5-methyl-6,7-difluoro-1-methylthio-4H-quinoxalino[1,2-c]-thiazoliumiodide (0.5 g) at 10° C., and the mixture is stirred at room temperaturefor 30 minutes. The reaction mixture is evaporated to dryness underreduced pressure. To the residue is then added water and the undissolvedsubstance is separated by filtration, washed with water, dried, andrecrystallized from hexane ethyl acetate to give the title compound(0.34 g) as yellow crystals.

M.p. 146°-148° C.

NMR (CDCl₃) δ: 1.2 (6H, t, J=7Hz), 3.1 (3H, d, J=4.5Hz), 3.9 (4H, q,J=7Hz), 4.0 (2H, s), 6.5 (1H, t, J=1Hz), 6.8 (1H, dt, J=8Hz, J=9Hz), 7.3(1H, ddd, J=2Hz, J=5Hz, J=9Hz).

IR (KBr) ν_(max) cm⁻¹ : 1700, 1642, 1506, 1426, 1294, 1188, 1082.

Elementary analysis for C₁₈ H₁₈ N₂ O₄ SF₂ :

Calcd. (%): C,54.54; H,4.58; N,7.07

Found (%): C,54.45; H,4.61; N,6.89.

REFERENCE EXAMPLE 6 Preparation of diethyl(5-methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]quinoxalin-1-ylidene)malonate[compound

(VIII) in which R³ is ethyl]

To 5-methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]-quinoxaline-1 thione (cf.Reference Example 3) (18 g) are added toluene (110 ml) andtrichloromethyl chloroformate (9.74 ml), and the mixture is stirred at80° C. for 17 hours. The resulting precipitate is separated bydecantation, and to the precipitate containing small amount of tolueneare added acetonitrile (60 ml) and diethyl malonate (12.88 g). To themixture is added triethylamine (14.9 g) under ice cooling, and themixture is stirred at room temperature for 40 minutes. The reactionmixture is evaporated to dryness under reduced pressure. To the residueis then added water and the mixture is extracted with chloroform. Theextract is dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue is washed withisopropyl ether to give the title compound (24.3 g). This product isidentical with the diethyl(5-methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]quinoxalin-1-ylidene)-malonateobtained in Reference Example 5 in the physical properties.

REFERENCE EXAMPLE 7 Preparation of ethyl9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylate[compound (II-4) in which R³ is ethyl]

A mixture of diethyl(5-methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]quinoxalin-1-ylidene]malonate(cf. Reference Example 5) (1.2 g) and polyphosphoric acid (10 g) isstirred at 100° C. for 5 hours. To the reaction mixture is added coldwater, and the mixture is extracted with chloroform. The extract waswashed with a saline solution, dried over anhydrous magnesium sulfateand the solvent is distilled off under reduced pressure. The residue isrecrystallized from chloroform-ethanol to give the title compound (0.6g) as pale yellow crystals.

M.p. decomposed at around 285° C.

NMR (DMSO-d₆) δ: 1.3 (3H, t, J=7Hz), 3.2 (3H, d, J=5.5Hz), 4.3 (2H, q,J=7Hz), 4.5 (2H, d, J=1Hz), 7.3 (1H, s), 7.4 (1H, dd, J=7.5Hz,J=10.5Hz).

IR (KBr) ν_(max) cm⁻¹ : 3060, 1708, 1574, 1496, 1478, 1456, 1050.

Elementary analysis for C₁₆ H₁₂ N₂ O₃ SF₂ :

Calcd. (%): C,54.85; H,3.45; N,8.00

Found (%): C,54.65; H,3.59; N,7.97.

REFERENCE EXAMPLE 8 Preparation of9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound (II 3)]

To ethyl9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4carboxylate (1.6 g) is added conc. sulfuric acid (18 ml), and themixture is stirred at 85° C. for 6 hours. To the reaction mixture isadded ice, and the resulting precipitate is separated by filtration andwashed with water to give a product (1.25 g) as pale yellow powder. Thisproduct is recrystallized from dimethylsulfoxide-ethanol to give thetitle compound (1.0 g).

M.p. decomposed at around 262° C.

NMR (DMSO-d₆) δ: 3.2 (3H, d, J=6Hz), 4.6 (2H, s), 7.5 (1H, s), 7.6 (1H,dd, J=7Hz, J=9Hz), 15.6 (1H, bs).

IR (KBr) ν_(max) cm⁻¹ : 1690, 1552, 1506, 1480, 1472, 1456, 1404.

Elementary analysis for C₁₄ H₈ N₂ O₃ SF₂ :

Calcd. (%): C,52.17; H,2.50; N,8.69

Found (%): C,52.07; H,2.77; N,8.47.

REFERENCE EXAMPLE 9 Preparation of9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound (II-3)]

Dipropionyloxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 26 hereinafter) (0.5 g) is suspended in acetone (2 ml) andthereto is added conc. hydrochloric acid (0.15 ml), and the mixture isstirred at room temperature. The resulting solid product is collected byfiltration, washed with water, acetone and isopropyl ether in thisorder, and then recrystallized from dimethylsulfoxide-ethanol to givethe title compound (0.36 g).

This product is identical with9,1-(methylimino)-methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid obtained in Reference Example 8 in the physical properties.

REFERENCE EXAMPLE 10 Preparation of 2-methoxymethylmorpholine [compound(IX) in which R¹ is methoxy]

2-Methoxymethylmorpholine is prepared by the following two steps.

(1) 4-Benzyl-2-methoxymethylmorpholine

N-Benzylethanolamine (459 g) is mixed with 1,2-epoxy-3-methoxypropane(422 g) and the mixture is stirred at 50° C. for 16 hours and thereafterthe excess 1,2-epoxy-3-methoxypropane is distilled off under reducedpressure. The residue is dissolved in 1,4-dioxane (3 liters) and theretoare added powdery potassium hydroxide (692.5 g) andtris(3,6-dioxaheptyl)amine (11.4 g). To the mixture is added dropwisewith stirring a solution of p-toluenesulfonyl chloride (809.4 g) in1,4-dioxane (2 liters) over a period of 1.5 hour, during which thetemperature of the reaction mixture raises and the solvent is refluxed.After the dropwise addition, the mixture is stirred for 2 hours, and theundissolved materials are filtered off and washed with ethyl acetate.The filtrate and the washing liquid are combined and distilled underreduced pressure to remove the solvent. To the residue are added water(600 ml) and conc. hydrochloric acid (300 ml) to make acidic. Theaqueous layer is washed with ethyl acetate, made strongly basic byadding sodium hydroxide (160 g) under ice cooling and extracted withethyl acetate. The ethyl acetate layer is washed with saturated salinesolution, dried over anhydrous magnesium sulfate and distilled underreduced pressure to remove the solvent. The obtained residue isdistilled under reduced pressure to give the title compound (391.3 g) ascolorless liquid.

B.p. 103° C./0.25 mmHg.

Elementary analysis for C₁₃ H₁₉ NO₂ :

Calcd. (%): C,70.56; H,8.65; N,6.33

Found (%): C,70.53; H,8.70; N,6.19.

(2) 2-Methoxymethylmorpholine [compound (IX) in which R¹ is methoxy]

N-Benzyl-2-methoxymethylmorpholine (412.3 g) is dissolved in methanol (2liters), and thereto is added 10% palladium-carbon (33 g), and themixture is stirred under hydrogen pressure of 9 kg/cm² at 100° C. Aftercompletion of the reaction, palladium-carbon is filtered off, and thesolvent is distilled off under atmospheric pressure to give a paleyellow oily substance. The oily substance is distilled under reducedpressure to give the title compound (212.3 g) as colorless liquid.

B.p. 90° C./19 mmHg.

NMR (CDCl₃) δ: 2.0 (1H, bs), 2.6 (1H, dd, J=12Hz, J=10.5Hz), 2.8-3.0(3H, m), 3.4 (3H, s), 3.3-3.5 (2H, m), 3.6-3.7 (2H, m), 3.9-4.0 (1H, m).

REFERENCE EXAMPLE 11 Preparation of (2S)-2-methoxymethylmorpholinehydrochloride [compound (IX) in which R¹ is methoxy, and 2-position isS-configuration, hydrochloride thereof]

(2S)-2-Methoxymethylmorpholine hydrochloride is prepared by thefollowing three steps.

(1) 4-Benzyl-2-(p-toluenesulfonyloxymethyl)-morpholine:

4-Benzyl-2-hydroxymethylmorpholine (prepared in the same manner asdescribed in Synthetic Communication, Vol. 10, pages 59-73, 1980) (51 g)is dissolved in pyridine (100 ml) and thereto is added p-toluenesulfonylchloride (51.7 g) under ice cooling, and the mixture is stirred at roomtemperature for 12 hours. The precipitated crystals are separated byfiltration and washed with ethyl acetate to give hydrochloride of thetitle compound (70 g). The product (50 g) is suspended in water (200 ml)and the mixture is adjusted to pH 10 with 2N aqueous sodium hydroxide,and extracted with ether. The extract is washed with water, dried overanhydrous sodium sulfate and concentrated under reduced pressure to givethe title compound (43 g).

NMR (CDCl₃) δ: 1.7-2.9 (4H, m), 2.4 (3H, s), 3.4-4.1 (5H, m), 3.5 (2H,s), 7.2-7.5 (7H, m), 7.8 (2H, d, J=9Hz).

(2) (2S)-4-Benzyl-2-methoxymethylmorpholine

In the same manner as described in Journal of Medicinal Chemistry, Vol.19, pages 1074-1076, 1976, the above4-benzyl-2-(p-toluenesulfonyloxymethyl)morpholine is glutamic acid(prepared as disclosed in Journal of the Chemical Society, page 706,1940) to give(2S)-4-benzyl-2-(p-toluenesulfonyloxymethyl)morpholine.N-(p-toluenesulfonyl)-L-glutamicacid salt.

This compound (10 g) is dissolved in methanol (10 ml) and thereto isadded 28% sodium methoxide/methanol (53 g), and the mixture is refluxedfor 18 hours. The reaction mixture is adjusted to pH 8 with dilutedhydrochloric acid and extracted with ether. The extract is washed withwater, dried over anhydrous sodium sulfate, and distilled under reducedpressure to remove the solvent. The residue is purified by silica gelcolumn chromatography (eluent, chloroform), and then distilled underreduced pressure to give the title compound (3.5 g) as colorless liquid.

B.p. 119° C./0.25 mmHg.

NMR (CDCl₃) δ: 2.0 (1H, dd, J=11Hz, J=10.5Hz), 2.2 (1H, td, J=11Hz,J=3Hz), 2.6 2.7 (1H, m), 2.7 (1H, dt, J=11Hz, J=2Hz), 3.3-4.0 (7H, m),3.4 (3H, s), 7.2-7.4 (5H, m).

Elementary analysis for C₁₃ H₁₉ NO₂ :

Calcd. (%): C,70.56; H,8.65; N,6.33

Found (%): C,70.33; H,8.84; N,6.29.

[α]_(D) ²¹ +28.1° (c=1.0, CH₃ OH).

(3) (2S)-2-methoxymethylmorpholine hydrochloride

(2S)-4-Benzyl-2-methoxymethylmorpholine (3 g) is dissolved in ethanol(50 ml) and thereto are added 4N hydrogen chloride/dioxane (3.4 ml) and10% palladium-carbon (0.3 g), and the mixture is stirred under hydrogenpressure of 5 kg/cm² at 40° C. for 6 hours. After removingpalladium-carbon, the solvent is distilled off under reduced pressure.The residue is recrystallized from ethyl acetate-methanol to give thetitle compound (1.8 g).

M.p. 141°-142° C.

NMR (CDCl₃) δ: 3.0-3.2 (2H, m), 3.4 (3H, s), 3.3-3.6 (4H, m), 4.0 4.2(3H, m), 10.0 (2H, br).

Elementary analysis for C₆ H₁₃ NO₂.HCl:

Calcd. (%): C,42.99; H,8.42; N,8.36

Found (%): C,43.10; H,8.40; N,8.28.

[α]_(D) ²⁰ -1.7° (c=1.0, CH₃ OH).

REFERENCE EXAMPLE 12 Preparation of (2R)-2-methoxymethylmorpholinehydrochloride [compound (IX) in which R¹ is methoxy, and 2-position isR-configuration, hydrochloride thereof]

(2R)-2-Methoxymethylmorpholine hydrochloride is prepared by thefollowing two steps.

(1) (2R)-4-Benzyl-2-methoxymethylmorpholine:

From the mother liquor in the resolution in Reference Example 11-(2), afraction rich in (2R)-4-benzyl -2-(p-toluenesulfonyloxymethyl)morpholineis recovered, and in the same manner as described in Journal ofMedicinal Chemistry, Vol. 19, pages 1074-1076, 1976, the above productis subjected to resolution with N-(p-toluenesulfonyl)-D-glutamic acid(prepared by the method as disclosed in Journal of the Chemical Society,page 706, 1940) to give(2R)-4-benzyl-2-(p-toluenesulfonyloxymethyl)morpholine.N-(p-toluenesulfonyl)-D-glutamicacid salt.

This compound is reacted with sodium methoxide in the same manner asdescribed in Reference Example 11-(2) to give the title compound.

B.p. 120° C./0.45 mmHg.

NMR (CDCl₃) δ: 2.0 (1H, dd, J=11Hz, J=10.5Hz), 2.2 (1H, td, J=11Hz,J=3Hz), 2.6-2.7 (1H, m), 2.7 (1H, dt, J=11Hz, J=2Hz), 3.3-4.0 (7H, m),3.4 (3H, s), 7.2-7.4 (5H, m).

Elementary analysis for C₁₃ H₁₉ NO₂ :

Calcd. (%): C,70.56; H,8.65; N,6.33

Found (%): C,70.38; H,8.84; N,6.26.

[α]_(D) ²¹ -27.9° (c=1.0, CH₃ OH).

(3) (2R)-2-methoxymethylmorpholine hydrochloride

In the same manner as described in Reference Example 11-(3) except that(2R)-4-benzyl-2-methoxymethylmorpholine is used instead of(2S)-4-benzyl-2-methoxymethylmorpholine, there is obtained the titlecompound.

M.p. 141°-142° C.

NMR (CDCl₃) δ: 3.0-3.2 (2H, m), 3.4 (3H, s), 3.3-3.6 (4H, m), 4.0 4.2(3H, m), 10.0 (2H, br).

Elementary analysis for C₆ H₁₃ NO₂.HCl:

Calcd. (%): C,42.99; H,8.42; N,8.36

Found (%): C,42.95; H,8.39; N,8.34.

[α]_(D) ²⁰ +1.9° (c=1.0, CH₃ OH).

REFERENCE EXAMPLE 13 Preparation of 2-fluoromethylmorpholinehydrochloride [compound (IX) in which R¹ is fluorine atom, hydrochloridethereof]

2-Fluoromethylmorpholine is prepared by the following two steps.

(1) N-Benzyl-2-fluoromethylmorpholine hydrochloride [compound (XII-1) inwhich R⁶ is fluorine atom[:

A mixture of N-benzylethanolamine (10 g) and epifluorohydrin (10 g) isstirred at 45° C. for 3 hours and thereafter the excess epifluorohydrinis distilled off under reduced pressure. To the obtained oily substanceis added conc. sulfuric acid (20 ml), and the mixture is stirred at 150°C. for one hour. The reaction mixture is allowed to cool and then pouredinto ice water. The solution is made basic by adding aqueous sodiumhydroxide and extracted with toluene. The extract is washed with salinesolution, dried over anhydrous magnesium sulfate and distilled underreduced pressure to remove the solvent. To the obtained oily substanceis added 4N hydrogen chloride/ethyl acetate solution, and theprecipitated solid substance is collected by filtration and washed withether to give the title compound (8.9 g).

M.p. 160°-163° C.

NMR (D₂ O) δ: 3.1-3.3 (2H, m), 3.5-3.6 (2H, m), 3.9-4.2 (3H, m), 4.4-4.7(4H, m), 7.5 (5H, s).

Elementary analysis for C₁₂ H₁₆ NOF.HCl:

Calcd. (%): C,58.66; H,6.97; N,5.70

Found (%): C,58.45; H,6.82; N,5.63.

(2) 2-Fluoromethylmorpholine hydrochloride

To a solution of N-benzyl-2-fluoromethylmorpholine hydrochloride (1.46g) in ethanol (85 ml) is added 10% palladium-carbon (0.2 g), and themixture is stirred under hydrogen atmosphere (maximum hydrogen pressure:6 kg/cm²) at room temperature. After completion of absorption ofhydrogen gas, palladium-carbon is filtered off, and the filtrate isconcentrated under reduced pressure. To the residue are added ether (2ml) and ethanol (0.5 ml), and the precipitated crystals are separated byfiltration and dried under reduced pressure to give the title compound(0.6 g).

NMR (D₂ O) δ: 3.1-3.5 (4H, m), 3.9-4.2 (3H, m), 4.5-4.7 (2H, m).

IR (KBr) ν_(max) cm⁻¹ : 2920, 1460, 1086, 1028.

REFERENCE EXAMPLE 14 Preparation of 2-methylmorpholine hydrochloride[compound (IX) in which R¹ is hydrogen atom, hydrochloride thereof]

2-Methylmorpholine hydrochloride is prepared by the following two steps.

(1) N-Benzyl-2-methylmorpholine [compound (XII-1) in which R⁶ ishydrogen atom]:

A mixture of N-benzylethanolamine (14 g) and propylene oxide (16.1 g) isstirred at room temperature for 55.5 hours and thereafter the excesspropylene oxide is distilled off under reduced pressure. To theresulting oily substance is added conc. sulfuric acid (30 ml), and themixture is stirred at 145° C. for 30 minutes. The reaction mixture isallowed to cool and poured into ice water. The mixture is made basic byadding potassium hydroxide (150 g) and extracted with ethyl acetate. Theextract is washed with saline solution and dried over anhydrous sodiumsulfate. The solvent is distilled off under reduced pressure to give thetitle compound (12.5 g) as oily substance.

NMR (CDCl₃) δ: 1.1 (3H, d, J=6.5Hz), 1.6-2.9 (4H, m), 3.4 (2H, s),3.4-4.0 (3H, m), 7.3 (5H, s).

(2) 2-Methylmorpholine hydrochloride:

N-Benzyl-2-methylmorpholine (6.5 g) and 10% palladium-carbon (1.1 g) areadded to acetic acid (60 ml), and the mixture is stirred under hydrogenatmosphere (maximum hydrogen pressure: 6 kg/cm²) at room temperature for60 hours. Palladium-carbon is filtered off, and to the filtrate areadded 4N hydrogen chloride/ethyl acetate solution (15 ml), and themixture is concentrated under reduced pressure. To the concentrate isadded toluene, and the mixture is evaporated to dryness. This procedureis repeated twice to give the title compound (4.6 g) as colorlesspowder.

NMR (D₂ O) δ: 1.2 (3H, d, J=6.5Hz), 2.7-4.3 (7H, m).

REFERENCE EXAMPLE 15 Preparation of 2-chloromethylmorpholinehydrochloride [compound (IX) in which R¹ is chlorine atom, hydrochloridethereof]

N-Benzyl-2-chloromethylmorpholine prepared in the same manner asdescribed in Synthetic Communication, Vol. 10 (1), pages 59-73, 1980(1.5 g) is dissolved in 3N hydrogen chloride/ethanol (10 ml), andthereto is added 10% palladiumcarbon (330 mg), and the mixture isstirred under hydrogen pressure of 6 kg/cm² at room temperature. Aftercompletion of absorption of hydrogen gas, palladium-carbon is filteredoff, and the filtrate is concentrated under reduced pressure. To theresidue are added ether (2 ml) and ethanol (0.5 ml). The precipitatedcrystals are separated by filtration and dried under reduced pressure togive the title compound (1.4 g).

NMR (D₂ O) δ: 2.9-3.1 (4H, m), 3.5-4.0 (5H, m).

REFERENCE EXAMPLE 16 Preparation of 2-hydroxymethylmorpholinehydrochloride [compound (IX) in which R¹ is hydroxy, hydrochloridethereof]

N-Benzyl-2-hydroxymethylmorpholine prepared in the same manner asdescribed in Synthetic Communication, Vol. 10 (1), pages 59-73, 1980(1.3 g) is subjected to hydrogenolysis in hydrogen chloride-containingethanol in the same manner as described in Reference Example 15 to give2-hydroxymethylmorpholine hydrochloride (1.3 g).

NMR (D₂ O) δ: 3.0-3.2 (4H, m), 3.5-4.0 (5H, m).

REFERENCE EXAMPLE 17 Preparation of 2-methoxymethylmorpholinehydrochloride [compound (IX) in which R¹ is methoxy, hydrochloridethereof]

2-Methoxymethylmorpholine hydrochloride is prepared by the following twosteps.

(1) 4-Benzyl-2-methoxymethylmorpholine:

To a sodium methoxide solution prepared from sodium (0.58 g) andanhydrous methanol (28 ml) are added N-benzyl-2-chloromethylmorpholine(cf Reference Example 15) (2.9 g) and sodium iodide (2.8 g), and themixture is refluxed for 24 hours and thereafter stirred in a pressurevessel at 165°-170° C. for 23 hours. The solvent is distilled off underreduced pressure. To the residue is added chloroform, and the insolublematerials are filtered off. The fitrate is evaporated to dryness underreduced pressure, and the residue is purified by silica gel columnchromatography (eluent, chloroform-methanol=100:1) to give the titlecompound (1.05 g).

NMR (CDCl₃) δ: 2.0 (1H, t, J=11Hz), 2.2 (1H, dt, J=3Hz, J=11Hz), 2.6-2.8(2H, m), 3.4 (3H, s), 3.3-3.5 (2H, m), 3.5 (2H, s), 3.7-3.8 (2H, m),3.9-4.0 (1H, m), 7.2-7.4 (5H, m).

(2) 2-Methoxymethylmorpholine hydrochloride [compound (IX) in which R¹is methoxy]:

N-Benzyl-2 methoxymethylmorpholine is subjected to hydrogenolysis inhydrogen chloride-containing ethanol in the same manner as described inReference Example 15 to give 2-methoxymethylmorpholine hydrochloride.

NMR (D₂ O) δ: 3.0-3.3 (2H, m), 3.3-3.4 (2H, m), 3.4 (3H, s), 3.5-3.7(2H, m), 3.8-4.2 (3H, m).

REFERENCE EXAMPLE 18 Preparation of 2-hydroxymethyl-1-methylpiperazinediacetate [compound (X) in which R² is hydroxy and R³ is methyl,diacetate thereof]

2-Hydroxymethyl-1-methylpiperazine diacetate is prepared by thefollowing four steps.

(1) Ethyl 1-benzylpiperazine-3-carboxylate [compound (XV)]:

To a suspension of ethyl piperazine-2-carboxylate diacetate (35.0 g) inmethylene chloride (400 ml) are added drowise a solution of1,8-diazabicyclo[5.4.0]-7-undecene (60 ml) in methylene chloride (50 ml)and a solution of benzyl bromide (15.0 ml) in methylene chloride (50 ml)with stirring under ice cooling and thereafter the mixture is stirred atroom temperature for 1.5 hour. The reaction mixture is washed twice withwater (150 ml). The organic layer is dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue is purified by silica gel column chromatography (eluent,chloroform-methanol=50:1) to give the title compound (18.6 g).

Mass spectrum (m/e): 248 (M⁺).

NMR (CDCl₃) δ: 1.2 (3H, t, J=7Hz), 2.1 (1H, s), 2.2-2.3 (1H, m), 2.3-2.5(1H, m), 2.5-2.6 (1H, m), 2.8-3.0 (2H, m), 3.0-3.1 (1H, m), 3.5 (1H, d,J=13Hz), 3.6 (1H, d, J=13Hz), 3.6 (1H, dd, J=3Hz, J=8Hz), 4.2 (2H, q,J=7Hz), 7.2-7.3 (5H, m).

(2) Ethyl 4-benzyl-1-methylpiperazine-2-carboxylate [compound (XVI) inwhich R³ is methyl]:

To ethyl 4-benzylpiperazine-3-carboxylate (4.25 g) are added formalin(2.1 ml) and formic acid (0.97 ml) with stirring at room temperature,and the mixture is further stirred at 95°-100° C. for 30 minutes. Thereaction mixture is diluted with water and adjusted to pH 11 by adding1N aqueous sodium hydroxide and then extracted with chloroform (200 ml).The organic layer is washed with water, dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent togive the title compound (4.45 g).

Mass spectrum (m/e): 262 (M⁺).

NMR (CDCl₃) δ: 1.2 (3H, t, J=7Hz), 2.3 (3H, s), 2.3-2.5 (3H, m), 2.6-2.7(1H, m), 2.8-2.9 (1H, m), 2.9-3.0 (1H, m), 3.0 (1H, dd, J=3Hz, J=9Hz),3.5 (1H, d, J=13Hz), 3.6 (1H, d, J=13Hz), 4.2 (2H, q, J=7Hz), 7.2-7.3(5H, m).

(3) 4-Benzyl-2-hydroxymethyl-1-methylpiperazine [compound (XIV-1) inwhich R³ is methyl]:

To a suspension of lithium aluminum hydride (0.98 g) in tetrahydrofuran(50 ml) is added dropwise a solution of ethyl4-benzyl-1-methylpiperazine-2-carboxylate (4.54 g) in tetrahydrofuran(10 ml) with stirring at room temperature and thereafter the mixture isfurther stirred for 50 minutes. To the reaction mixture is added icewith stirring under ice cooling to decompose lithium aluminum hydride.The precipitated insoluble materials are filtered off. The filtrate isevaporated to dryness. The residue is dissolved in chloroform, driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent to give the title compound (2.95 g).

NMR (CDCl₃ +D₂ O) δ: 2.2-2.4 (2H, m), 2.3 (3H, s), 2.4-2.5 (1H, m),2.6-2.8 (1H, m), 2.8-2.9 (1H, m), 2.5-3.2 (1H, br), 3.4 (1H, dd, J=2Hz,J=11Hz), 3.5 (2H, s), 3.9 (1H, dd, J=4Hz, J=11Hz), 7.2-7.3 (5H, m).

(4) 2-Hydroxymethyl-1-methylpiperazine diacetate [compound (X) in whichR² is hydroxy and R³ is methyl, diacetate thereof]:

To a solution of 4-benzyl-2-hydroxymethyl-1-methylpiperazine (0.90 g) inacetic acid (10 ml) is added 10% palladium-carbon (180 mg), and themixture is stirred under hydrogen gas (5 kg/cm²) at room temperature for23 hours. Palladium-carbon is filtered off, and the filtrate isevaporated to dryness. To the residue is added ethanol (20 ml), and themixture is evaporated to dryness. The residue is again dissolved inethanol, and the solvent is distilled off under reduced pressure. Thisprocedure is repeated four times to give the title compound (0.92 g).

NMR (CDCl₃) δ: 2.0 (6H, s), 2.5 (3H, s), 2.3-4.0 (10H, m), 8.2 (3H, s).

REFERENCE EXAMPLE 19 Preparation of 2-methoxymethyl-1-methylpiperazinedihydrochloride [compound (X) in which R² is methoxy and R³ is methyl,dihydrochloride thereof]

2-Methoxymethyl-1-methylpiperazine dihydrochloride is prepared by thefollowing three steps.

(1) 4-Benzyl-2-chloromethyl-1-methylpiperazine [compound (XIV-2) inwhich R³ is methyl and X¹ is chlorine atom]:

4-Benzyl-2-hydroxymethyl-1-methylpiperazine (cf. Reference Example18-(3)] (2 g) is dissolved in carbon tetrachloride (35 ml) and theretois added dropwise thionyl chloride (1.33 ml) diluted with carbontetrachloride (5 ml), and the mixture is stirred at 70° C. for one hour.The reaction mixture is allowed to cool till room temperature and isadjusted to pH 9 by adding 1N aqueous sodium hydroxide and then isextracted with chloroform. The organic layer is washed with water, driedover anhydrous sodium sulfate and the solvent is distilled off underreduced pressure. The residue is purified by silica gel columnchromatography (eluent, chloroform-methanol=50:1) to give the titlecompound (1.13 g).

Mass spectrum (m/e): 238 (M⁺).

NMR (CDCl₃) δ: 2.3-2.5 (5H, m), 2.4 (3H, s), 2.6-2.7 (1H, m), 2.7-2.9(2H, m), 3.5-3.6 (3H, m), 3.6 (1H, dd, J=6Hz, J=12Hz), 7.2-7.4 (5H, m).

(2) 4-Benzyl-2-methoxymethyl-1-methylpiperazine [compound (XIV-3) inwhich R³ is methyl]:

To a solution of sodium methoxide in methanol, which is prepared fromsodium (0.24 g) and anhydrous methanol (50 ml), are added4-benzyl-2-chloromethyl-1-methylpiperazine (1.2 g) and sodium iodide(0.9 g), and the mixture is stirred at 60°-65° C. for 16 hours. Thesolvent is distilled off under reduced pressure, and the resultingresidue is dissolved in acetone and insoluble materials are filteredoff. The filtrate is evaporated to dryness, and the residue is purifiedby silica gel column chromatography (eluent, chloroform-methanol=50:1)to give the title compound (1.0 g).

Mass spectrum (m/e): 234 (M⁺).

NMR (CDCl₃) δ: 2.1-2.4 (4H, m), 2.3 (3H, s), 2.7-2.9 (3H, m), 3.3 (3H,s), 3.3-3.4 (2H, m) 3 5 (1H, d J=13Hz), 3.51 (1H, d, J=13Hz), 7.2-7.4(5H, m).

(3) 2-Methoxymethyl 1-methylpiperazine dihydrochloride [compound (X) inwhich R² is methoxy and R³ is methyl, dihydrochloride thereof]:

To a solution of 4-benzyl-2-methoxymethyl-1-methylpiperazine (0.95 g) inacetic acid (15 ml) is added 10% palladium-carbon (0.29 g), and themixture is stirred under hydrogen gas (maximum hydrogen pressure: 5kg/cm²) for 17 hours. Palladium-carbon is filtered off, and to thefiltrate is added 2N hydrochloric acid (6 ml), and the mixture isevaporated to dryness under reduced pressure. To the residue is addedethanol (20 ml) and the mixture is evaporated to dryness under reducedpressure. This procedure is repeated five times to give the titlecompound (1.01 g).

NMR (D₂ O) δ: 3.0 (3H, s), 3.4 (3H, s), 3.4-3.7 (4H, m), 3.7-3.9 (4H,m), 4.0 (1H, dd, J=3Hz, J=12Hz).

REFERENCE EXAMPLE 20 Preparation of 2-fluoromethyl-1-methylpiperazinedihydrochloride [compound (X) in which R² is fluorine atom and R³ ismethyl, dihydrochloride thereof]:

2-Fluoromethyl-1-methylpiperazine dihydrochloride is prepared by thefollowing two steps.

(1) 4-Benzyl-2-fluoromethyl-1-methylpiperazine [compound (XIV-4) inwhich R³ is methyl and X² is fluorine atom]:

A mixture of 4-benzyl-2-chloromethyl-1-methylpiperazine [cf. ReferenceExample 19-(1)] (2.14 g), potassium bifluoride (2.10 g) and ethyleneglycol (20 ml) is stirred at 135° C. for 2 hours and 25 minutes. Thereaction mixture is cooled till room temperature and adjusted to pH 9 byadding water and saturated aqueous sodium carbonate solution and then isextracted with ethyl acetate (300 ml). The organic layer is washed withwater and thereto is added dilute hydrochloric acid, and the mixture isextracted with water (150 ml). The aqueous layer is washed with ethylacetate and adjusted to pH 9 by adding saturated aqueous sodiumcarbonate solution and then extracted with ethyl acetate (300 ml). Theorganic layer is washed with water and saturated saline solution, driedover anhydrous magnesium sulfate and evaporated to dryness under reducedpressure. The residue is purified by silica gel column chromatography(eluent, firstly with chloroform, and then withchloroform-methanol=50:1) to give the title compound (0.19 g).

NMR (CDCl₃) δ: 2.1 (1H, t, J=10Hz), 2.4 (3H, d, J=1Hz), 2.2-2.6 (3H, m),3.5 (2H, s), 4.4 (1H, ddd, J=4Hz, 10Hz, 48Hz), 4.5 (1H, ddd, J=4Hz,10Hz, 48Hz), 7.2-7,4 (5H, m).

(2) 2-Fluoromethyl-1-methylpiperazine dihydrochloride [compound (X) inwhich R² is fluorine atom and R³ is methyl, dihydrochloride thereof]:

To a solution of 4-benzyl-2-fluoromethyl-1-methylpiperazine (0.2 g) inacetic acid (15 ml) is added 10% palladium-carbon (0.13 g), and themixture is stirred under hydrogen gas (maximum hydrogen pressure: 5kg/cm²) for 2 hours. The reaction mixture is filtered and to thefiltrate is added 2N hydrochloric acid (1.5 ml), and the mixture isevaporated to dryness under reduced pressure. To the residue is addedethanol (10 ml) and the mixture is further evaporated to dryness. Thisprocedure is repeated five times to give the title compound (0.17 g) assyrup.

REFERENCE EXAMPLE 21 Preparation of(6R)-1,8-diaza-4-oxabicyclo[4.4.0]-decane [compound (XI)]

(6R)-1,8-Diaza-4-oxabicyclo[4.4.0]decane is prepared by the followingsix steps.

(1) N-tert-Butyloxycarbonyl-L-serine benzylamide [compound (XVIII)]:

N-tert-Butyloxycarbonyl-L-serine (49.3 g) is dissolved indichloromethane (400 ml) and thereto are added benzylamine (30.6 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.2 g)with stirring under ice cooling, and the mixture is further stirred atroom temperature for 72 hours. The reaction mixture is washed withwater, 0.5N hydrochloric acid, water and saturated aqueous sodiumhydrogen carbonate solution in this order, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresulting solid is recrystallized from hexane-ethyl acetate to give thetitle compound (40.9 g).

M.p. 101°-103° C.

NMR (CDCl₃) δ: 1.4 (9H, s), 3.5-4.5 (6H, m), 5.8 (1H, d, J=6.5Hz),7.0-7.4 (1H, m), 7.2 (5H, s).

(2) N-tert-Butyloxycarbonyl-O-carboxymethyl-L-serine benzylamide[compound (XIX)]:

N-tert-Butyloxycarbonyl-L-serine benzylamide (5.6 g) is dissolved intetrahydrofuran and thereto are added bromoacetic acid (2.9 g) andpotassium tert-butoxide (4.7 g) under ice cooling, and the mixture isstirred at room temperature for 72 hours. The solvent is distilled offunder reduced pressure and to the residue is added 1% aqueous potassiumhydroxide (50 ml), and the mixture is washed with chloroform (50 ml)three times. The aqueous layer is adjusted to pH 3.5 with 1Nhydrochloric acid and extracted with chloroform (150 ml). The chloroformlayer is washed with saturated aqueous saline solution, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The resulting solid is washed with ether to give the titlecompound (5.7 g).

NMR (CDCl₃) δ: 1.4 (9H, s), 3.4-4.6 (7H, m), 6.3 (1H, m), 7.2 (5H, s),7.5 (1H, m), 10.6 (1H, s).

(3) N-tert-Butyloxycarbonyl-O-methoxycarbonylmethyl-L-serine benzylamide[compound (XX) in which R³ is methyl]:

N-tert-Butyloxycarbonyl-O-carboxymethyl-L-serine benzylamide (40.5 g)and methyl iodide (19.6 g) are dissolved in N,N-dimethylformamide (200ml) and thereto is added potassium carbonate (9.5 g), and the mixture isstirred at room temperature for 2 hours. The solvent is distilled offunder reduced pressure, and to the residue is added water (200 ml), andthe mixture is extracted with chloroform (600 ml). The chloroform layeris washed with aqueous sodium thiosulfate and saturated aqueous salinesolution in this order, dried over anhydrous sodium sulfate and thesolvent is distilled off under reduced pressure to give the titlecompound (40 g) as oil.

NMR (CDCl₃) δ: 1.4 (9H, s), 3.7 (3H, s), 3.6-4.5 (5H, m), 4.1 (2H, s),5.7 (1H, d, J=6.5Hz), 7.1 (1H, m), 7.3 (5H, s).

(4) (S)-N-Benzyl-5-oxo-3-morpholinecarboxamide [compound (XXI)]:

N-tert-Butyloxycarbonyl-O-methoxycarbonylmethyl-L-serine benzylamide (47g) is dissolved in 4N hydrogen chloride/dioxane (100 ml) and the mixtureis stirred under ice cooling for one hour. Thereafter, the solvent isdistilled off under reduced pressure. To the residue is added methanol(50 ml), and the solvent is again distilled off under reduced pressure.The residue is dissolved in methanol (200 ml) and thereto is addedpotassium carbonate (15.4 g), and the mixture is stirred at roomtemperature for 20 hours. After completion of the reaction, insolublematerials are filtered off, and the solvent is distilled off underreduced pressure. To the residue is added water (50 ml), and the mixtureis extracted with chloroform (600 ml). The chloroform layer is driedover anhydrous sodium sulfate, and distilled under reduced pressure toremove the solvent. The residue is recrystallized from ethanol to givethe title compound (18 g).

M.p. 130°-133° C.

NMR (CDCl₃) δ: 3.8 (1H, dd, J=4Hz, J=12Hz), 3.9-4.0 (3H, m), 4.2 (1H,m), 4.4 (2H, d, J=3Hz), 7.2-7.3 (5H, m).

Elementary analysis for C₁₂ H₁₄ N₂ O₃ :

Calcd. (%): C,61.53; H,6.02; N,11.96

Found (%): C,61.37; H,5.93; N,11.96.

(5) (R)-N-Benzyl-N (3-morpholinylmethyl)amine [compound (XXII)]:

To a suspension of (S)-N-benzyl-5 oxo-3-morpholine carboxamide (3.0 g)in toluene (30 ml) is added drowise sodium bis(2-methoxyethoxy)aluminumhydride (20 g) under ice cooling, and the mixture is stirred at roomtemperature for 20 hours. To the reaction mixture is added water whilekeeping the temperature at lower than 20° C., and the precipitatedinsoluble materials are filtered off. The filtrate toluene layer isseparated, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent to give the title compound (2.0g) as oil.

NMR (CDCl₃) δ: 2.4-3.9 (9H, m), 3.8 (2H, s), 7.2 (5H, s).

(6) (6R) N Benzyl-1,8-diaza-4-oxabicyclo[4.4.0]-decane [compound(XXIII)]:

(R)-N-Benzyl-N-(3-morpholinylmethyl)amine (1.0 g) is dissolved inN,N-dimethylformamide (10 ml) and thereto are added potassium carbonate(0.67 g) and 1,2-dibromoethane (1.0 g), and the mixture is stirred at50° C. for 16 hours. N,N-Dimethylformamide is distilled off underreduced pressure, and to the residue is added water (10 ml) and themixture is adjusted to pH 2.0 with 3N hydrochloric acid. The aqueouslayer is washed twice with ethyl acetate, adjusted to pH 8.0 withsaturated aqueous potassium hydrogen carbonate solution and thenextracted with ethyl acetate (50 ml). The extract is dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent to give the title compound (0.7 g) as oil.

NMR (CDCl₃) δ: 2.1-3.8 (13H, m), 3.5 (2H, s), 7.3 (5H, s).

(7) (6R)-1.8-Diaza-4-oxabicyclo[4.4.0]decane [compound (XI)]:

(6R)-N-Benzyl-1,8-diaza-4-oxabicyclo[4.4.0]decane (0.7 g) is dissolvedin ethanol, and thereto is added 10% palladium-carbon (80 mg), and themixture is subjected to hydrogenolysis (maximum hydrogen pressure: 6kg/cm²). After completion of absorption of hydrogen gas, the catalyst isfiltered off, and the solvent is distilled off under reduced pressure togive the title compound (0.4 g) as oil.

NMR (CDCl₃) δ: 2.3-3.8 (13H, m).

REFERENCE EXAMPLE 22 Preparation of 2-ethoxymethylmorpholine [compound(IX) in which R¹ is ethoxy]

2-Ethoxymethylmorpholine is prepared by the following two steps.

(1) 4-Benzyl-2-ethoxymethylmorpholine:

4-Benzyl-2-(p-toluenesulfonyloxymethyl)morpholine hydrochloride [cf.Reference Example 11-(1)] (3 g) and sodium ethoxide (2 g) are added toethanol (150 ml), and the mixture is stirred at 70° C. for 24 hours. Thereaction mixture is concentrated under reduced pressure, and to theresidue is added saturated aqueous sodium hydrogen carbonate, and themixture is extracted with ethyl acetate. The extract is washed withsaturated aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and distilled under reduced pressure toremove the solvent. The residue is purified by silica gel columnchromatography (eluted by chloroform-methanol=40:1) and furthersubjected to bulb-to-bulb distillation (at 162° C., 0.4 mmHg) to givethe title compound (0.9 g) as colorless liquid.

NMR (CDCl₃) δ: 1.2 (3H, t, J=7Hz), 1.9 (1H, dd, J=11Hz, J=10.5Hz), 2.2(1H, td, J=11Hz, J=3Hz), 2.6-2.7 (1H, m), 2.8 (1H, dt, J=11Hz, J=2Hz),3.3-3.5 (6H, m), 3.6-3.8

(2H, m), 3.8-3.9 (1H, m), 7.2-7.4 (5H, m).

(2) 2-Ethoxymethylmorpholine:

4-Benzyl-2-ethoxymethylmorpholine (1.6 g) and 10% palladium-carbon (200mg) are added to ethanol (30 ml), and the mixture is stirred underhydrogen pressure of 5 kg/cm² for 24 hours. Palladium-carbon is filteredoff, and the solvent is distilled off under reduced pressure to give thetitle compound (0.7 g) as colorless liquid.

NMR (CDCl₃) δ: 1.2 (3H, t, J=7Hz), 3.0-3.2 (2H, m), 3.4-3.6 (6H, m),4.0-4.2 (3H, m), 8.2 (1H, br).

REFERENCE EXAMPLE 23 Preparation of 2-benzoyloxymethylmorpholinehydrochloride

2-Benzoyloxymethylmorpholine hydrochloride is prepared by the followingtwo steps.

(1) 4-Benzyl-2-benzoyloxymethylmorpholine hydrochloride:

4-Benzyl-2-hydroxymethylmorpholine (prepared by the method disclosed inSynthetic Communication, Vol. 10, pages 59-73, 1980) (200 g) andtriethylamine (122 g) are dissolved in chloroform (1.5 liter), andthereto is added dropwise benzoyl chloride (135 g) with stirring underice cooling. The mixture is stirred at room temperature for 16 hours andthereafter to the mixture is added water. The chloroform layer isseparated, washed with saturated aqueous sodium hydrogen carbonatesolution and saturated aqueous saline solution in this order, dried overanhydrous magnesium sulfate and distilled under reduced pressure toremove the solvent. The residue is dissolved in ethyl acetate (150 ml)and thereto is added 4N hydrogen chloride/ethyl acetate (250 ml) withstirring under ice cooling, and the precipitated crystals are separatedby filtration, washed with ethyl acetate and acetone in this order togive the title compound (240 g) as colorless crystals.

M.p. 168° C.

NMR (DMSO-d₆) δ: 3.0-3.3 (3H, m), 3.4-3.5 (1H, m), 3.9-4.1 (2H, m),4.3-4.5 (5H, m), 7.4-7.5 (3H, m), 7.5-7.6 (2H, m), 7.6-7.7 (3H, m), 8.0(2H, m), 11.9 (1H, bs).

Elementary analysis for C₁₉ H₂₁ NO₃.HCl.1/2H₂ O:

Calcd. (%): C,63.95; H,6.50; N,3.93

Found (%): C,63.95; H,6.76; N,4.00.

(2) 2-Benzoyloxymethylmorpholine hydrochloride:

10% Palladium-carbon (40 g) and 4-benzyl-2-benzoyloxymethylmorpholinehydrochloride (202 g) are added to a mixture of ethanol (600 ml) andwater (200 ml), and the mixture is stirred under hydrogen pressure of 10kg/cm² at 40° C. for 5 hours. Palladium-carbon is filtered off, and thesolvent is distilled off under reduced pressure. To the residue is addedethanol, and the mixture is distilled under reduced pressure. Thisprocedure is repeated three times. The resulting crystals are washedwith ether and recrystallized from chloroform-ethanol to give the titlecompound (91 g) as colorless crystals.

M.p. 196° C.

NMR (DMSO-d₆) δ: 2.9-3.1 (2H, m), 3.1-3.2 (1H, m), 3.3-3.4 (1H, m), 3.8(1H, td, J=12Hz, J=2Hz), 4.0 (1H, dd, J=12.5 Hz, J=3Hz), 4.1-4.2 (1H,m), 4.3-4.4 (2H, m), 7.5-7.6 (2H, m), 7.7 (1H, m). 8.0 (2H, m), 9.7 (2H,br).

Elementary analysis for C₁₂ H₁₅ NO₃.HCl.1/4H₂ O:

Calcd. (%): C,54.97; H,6.34; N,5.34

Found (%): C,54.89; H,6.31; N,5.30.

REFERENCE EXAMPLE 24 Preparation of (2S)-2-benzoyloxymethylmorpholinehydrochloride

(2S)-2-Benzoyloxymethylmorpholine hydrochloride is prepared by thefollowing two steps.

(1) (2S)-4-Benzyl-2-benzoyloxymethylmorpholine hydrochloride:

(2S)-4-Benzyl-2-(p-toluenesulfonyloxymethyl)-morpholine.N-(p-toluenesulfonyl)-L-glutamicacid salt [cf. Reference Example 11-(2)] (16.0 g) is added to an excessamount of aqueous sodium hydroxide solution, and the mixture isextracted with chloroform. The extract is dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent. Theobtained residue is dissolved in N,N-dimethylformamide (80 ml) andthereto are added benzoic acid (5.9 g) and potassium carbonate (6.7 g),and the mixture is stirred at 150° C. for 2 hours. The reaction mixtureis poured into ice water and extracted with chloroform. The extract iswashed with saturated aqueous saline solution, dried over anhydrousmagnesium sulfate and distilled under reduced pressure to remove thesolvent. The obtained residue is dissolved in acetone (10 ml) andthereto is added 4N hydrogen chloride/ethyl acetate (10 ml). Thepricipitate is separated by filtration and recrystallized from ethylacetate-ethanol to give the title compound (4.3 g).

M.p. 214°-217° C.

NMR (DMSO-d₆) δ: 3.0-3.3 (3H, m), 3.4-3.5 (1H, m), 4.0 (2H, d, J=7Hz),4.3-4.5 (5H, m), 7.4-7.5 (3H, m), 7.5-7.6 (2H, m), 7.7 (3H, m), 8.0 (2H,m), 12.1 (1H, bs).

Elementary analysis for C₁₉ H₂₁ NO₃.HCl:

Calcd. (%): C,65.61; H,6.37; N,4.03

Found (%): C,65.54; H,6.31; N,3.97.

[α]_(D) ²¹ +22.7° (c=1.0, CH₃ OH).

(2) (2S)-2-Benzoyloxymethylmorpholine hydrochloride:

(2S)-4-Benzyl-2-benzoyloxymethylmorpholine hydrochloride (4.0 g) isdissolved in methanol (32 ml) and thereto is added 10% palladium-carbon(0.8 g), and the mixture is stirred under hydrogen pressure of 5 kg/cm²at room temperature for 4 hours. Palladium-carbon is filtered off andthe solvent is distilled off under reduced pressure. The residue isrecrystallized from chloroform-ethanol to give the title compound (1.25g).

M.p. 170°-171° C.

NMR (D₂ O) δ: 3.2-3.3 (2H, m), 3.4 (1H, m), 3.5-3.6 (1H, m), 3.9-4.0(1H, m), 4.2-4.3 (2H, m), 4.4 (1H, dd, J=5Hz, J=12Hz), 4.6 (1H, dd,J=3Hz, J=12Hz), 7.5-7.6 (2H, m), 7.7-7.8 (1H, m), 8.0-8.1 (2H, m).

Elementary analysis for C₁₂ H₁₅ NO₃.HCl:

Calcd. (%): C,55.93; H,6.26; N,5.43.

Found (%): C,55.94; H,6.12; N,5.39.

REFERENCE EXAMPLE 25 Preparation of (2R)-2-benzoyloxymethylmorpholinehydrochloride

(2R)-2-Benzoyloxymethylmorpholine hydrochloride is prepared by thefollowing two steps.

(1) (2R)-4-Benzyl-2-benzoyloxymethylmorpholine hydrochloride:

In the same manner as described in Reference Example 24-(1) except that(2R)-4-benzyl-2-(p-toluenesulfonyloxymethyl)morpholine.N-(p-toluenesulfonyl)-D-glutamicacid salt [cf. Reference Example 12-(1)] is used instead of(2S)-4-benzyl-2-(p-toluenesulfonyloxymethyl)-morpholine.N-(p-toluenesulfonyl)-L-glutamicacid salt, there is prepared the title compound.

M.p. 214°-215° C.

NMR (DMSO-d₆) δ: 3.0-3.3 (3H, m), 3.4-3.5 (1H, m), 4.0 (2H, d, J=7Hz),4.3-4.5 (5H, m), 7.4-7.5 (3H, m), 7.5-7.6 (2H, m), 7.7 (3H, m), 8.0 (2H,m), 12.1 (1H, bs).

Elementary analysis for C₁₉ H₂₁ NO₃.HCl:

Calcd. (%): C,65.61; H,6.37; N,4.03

Found (%): C,65.49; H,6.39; N,3.96.

[α]_(D) ²¹ -23.2° (c=1.0, CH₃ OH).

(2) (2R)-2-Benzoyloxymethylmorpholine hydrochloride:

In the same manner as described in Reference Example 24-(2) except that(2R)-4-benzyl-2-benzoyloxymethylmorpholine hydrochloride is used insteadof (2S)-4-benzyl-2-benzoyloxymethylmorpholine hydrochloride, there isprepared the title compound.

M.p. 170°-171° C.

NMR (DMSO-d₆) δ: 2.9-3.1 (2H, m), 3.1-3.2 (1H, m), 3.3-3.4 (1H, m),3.8-3.9 (1H, m), 4.0 (1H, m), 4.1-4.2 (1H, m), 4.3-4.4 (2H, m), 7.5-7.6(2H, m), 7.7 (1H, m), 8.0 (2H, m), 9.8 (2H, bs).

Elementary analysis for C₁₂ H₁₅ NO₃.HCl:

Calcd (%): C,55.93; H,6.26; N,5.43

Found (%): C,55.88; H,6.18; N,5.41.

EXAMPLE 1 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound (I) in which Z is 2-methylmorpholino]

Diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 25 hereinafter) (0.75 g) is added to a mixture ofdimethylsulfoxide (30 ml), 2-methylmorpholine hydrochloride (cf.Reference Example 14) (0.4 g) and triethylamine (0.8 g), and the mixtureis stirred at 80° C. for 15 hours. Dimethylsulfoxide is distilled offunder reduced pressure, and the residue is washed with isopropyl etherand acetonitrile in this order, and thereto are added acetone (50 ml),water (10 ml) and conc. hydrochloric acid (5 ml). The mixture is stirredat room temperature for 2 hours. The resulting solid is washed withwater and ethanol in this order and recrystallized fromacetonitrile-ethanol to give the title compound (0.42 g).

M.p. decomposed at around 256° C.

NMR (DMSO-d₆) δ: 1.1 (3H, d, J=6Hz), 2.8 (3H, s), 2.9 3.0 (1H, m),3.2-3.5 (3H, m), 3.7-3.8 (2H, m), 3.8-3.9 (1H, m), 4.5 (2H, s), 7.6 (1H,s), 7.6 (1H, d, J=12.5Hz), 15.8 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1691, 1614, 1463.

Elementary analysis for C₁₉ H₁₈ N₃ O₄ SF:

Calcd. (%): C,56.57; H,4.50; N,10.42

Found (%): C,56.48; H,4.64; N,10.33.

EXAMPLE 2 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 2-hydroxymethylmorpholino]

Diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 25 hereinafter) (2 g) is added to a mixture ofdimethylsulfoxide (20 ml), 2-hydroxymethylmorpholine hydrochloride (cf.Reference Example 16) (1.5 g) and triethylamine (3.6 g), and the mixtureis stirred at 60° C. for 15 hours. Dimethylsulfoxide is distilled offunder reduced pressure, and to the residue are added acetone (5 ml),conc. hydrochloric acid (5 ml) and water (10 ml). The mixture is stirredat 60° C. for one hour. The resulting solid is washed with water andethanol in this order and recrystallized from chloroform - ethanol togive the title compound (0.8 g).

M.p. decomposed at around 257° C.

NMR (DMSO-d₆) δ: 2.8 (3H, s), 3.0-3.1 (1H, m), 3.2-3.8 (7H, m), 3.9-4.0(1H, m), 4.5 (2H, s), 4.8 (1H, t, J=5.5Hz), 7.6 (1H, s), 7.6 (1H, d,J=12.5Hz), 15.8 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1696, 1614, 1472, 1452, 1404.

Elementary analysis for C₁₉ H₁₈ N₃ O₅ SF:

Calcd. (%): C,54.41; H,4.33; N,10.02

Found (%): C,54.22; H,4.30; N,9.93.

EXAMPLE 3 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 2-fluoromethylmorpholino]

Diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 25 hereinafter) (3 g) is added to a mixture ofdimethylsulfoxide (60 ml), 2-fluoromethylmorpholine hydrochloride (cf.Reference Example 13) (3 g) and triethylamine (4.8 g), and the mixtureis stirred at 70° C. for 6 hours. Dimethylsulfoxide is distilled offunder reduced pressure, and to the residue are added acetone (9 ml),conc. hydrochloric acid (9 ml) and water (15 ml). The mixture is stirredat 50° C. for 6 hours. The resulting solid is washed with water andrecrystallized from acetonitrile-ethanol to give the title compound (1.3g).

M.p. decomposed at around 245° C.

NMR (DMSO-d₆) δ: 2.8 (3H, s), 3.1-3.3 (2H, m), 3.4-3.5 (2H, m), 3.7-4.0(3H, m), 4.5 (2H, s), 4.5 (2H, dd, J=4Hz, J=47Hz), 7.6 (1H, s), 7.6 (1H,d, J=12.5Hz), 15.8 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1694, 1614, 1468.

Elementary analysis for C₁₉ H₁₇ N₃ O₄ SF₂ :

Calcd. (%): C,54.15; H,4.06; N,9.97

Found (%): C,54.06; H,4.07; N,9.98.

EXAMPLE 4 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-chloromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 2-chloromethylmorpholino]

Diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 25 hereinafter) (1 g) is added to a mixture ofdimethylsulfoxide (50 ml), 2-chloromethylmorpholine hydrochloride (cf.Reference Example 15) (1.2 g) and triethylamine (1.6 g), and the mixtureis stirred at 70° C. for 6 hours. Dimethylsulfoxide is distilled offunder reduced pressure, and to the residue are added acetone (5 ml),conc. hydrochloric acid (3 ml) and water (10 ml). The mixture is stirredat 50° C. for one hour. The resulting solid is washed with water andethanol in this order and recrystallized from chloroform-methanol togive the title compound (0.1 g).

M.p. decomposed at around 250° C.

NMR (DMSO-d₆) δ: 2.8 (3H, s), 3.1-3.3 (2H, m), 3.4-3.5 (1H m) 3.5-3.6(1H, m), 3.7-3.9 (4H, m), 4 0-4 1 (1H, m), 4.5 (2H, s), 7.6 (1H, s), 7.6(1H, d, J=12.5Hz), 15.8 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1694, 1614, 1488.

Elementary analysis for C₁₉ H₁₇ N₃ O₄ SFCl:

Calcd. (%): C,52.12; H,3.91; N,9.60

Found (%): C,52.23; H,4.02; N,9.59.

EXAMPLE 5 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 2-methoxymethylmorpholino]

Diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 25 hereinafter) (0.9 g) is added to a mixture ofdimethylsulfoxide (20 ml), 2-methoxymethylmorpholine hydrochloride (cf.Reference Example 17) (0.8 g) and triethylamine (5.1 g), and the mixtureis stirred at 60° C. for 22 hours. Dimethylsulfoxide is distilled offunder reduced pressure, and to the residue are added acetone (15 ml),conc. hydrochloric acid (5 ml) and water (40 ml). The mixture is stirredat room temperature for one hour. The resulting solid is washed withwater and acetone in this order and recrystallized from acetonitrile togive the title compound (0.54 g).

M.p. decomposed at around 224° C.

NMR (CDCl₃) δ: 2.9 (3H, s), 3.3 (1H, ddd, J=2.5Hz, J=10.5Hz, J=12.5Hz),3.4 (3H, s), 3.4-3.6 (5H, m), 3.8-4.0 (2H, m), 4.0 (1H, dt, J=2Hz,J=11Hz), 4.4 (2H, s), 7.0 (1H, s), 7.6 (1H, d, J=12.5Hz), 15.4 (1H, bs).

IR (KBr) ν_(max) cm⁻¹ : 1696, 1616, 1490.

Elementary analysis for C₂₀ H₂₀ N₃ O₅ SF.1/4H₂ O:

Calcd. (%): C,54.85; H,4.72; N,9.59

Found (%): C,54.90; H,4.73; N,9.59.

EXAMPLE 6 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound (I) in which Z is 2-methylmorpholino]

This compound is prepared by the following two steps.

(1) Difluoro[9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane:

To a mixture of difluoro[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane(cf. Example 27 hereinafter) (0.75 g), 2-methylmorpholine hydrochloride(cf. Reference Example 14) (0.42 g) and dimethylsulfoxide (50 ml) isadded triethylamine (1.0 g), and the mixture is stirred at 80° C. for 20hours. The reaction mixture is concentrated to dryness under reducedpressure, and to the residue are added acetonitrile (10 ml) andisopropyl ether (20 ml), and the insoluble materials are separated byfiltration, washed with isopropyl ether, water and acetonitrile in thisorder to give the title compound (0.8 g).

M.p. above 280° C.

NMR (DMSO-d₆) δ: 1.1 (3H, d, J=6Hz), 2.8 (3H, s), 2.9-3.1 (1H, m),3.2-3.4 (1H, m), 3.5-3.6 (2H, m), 3.7-3.8 (2H, m), 3.9-4.0 (1H, m), 4.6(2H, s), 7.9 (1H, d, J=12.5Hz), 8.0 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1687, 1513, 1483, 1441.

Elementary analysis for C₁₉ H₁₇ N₃ O₄ SF₃ B.1/2H₂ O:

Calcd. (%): C,49.58; H,3.94; N,9.13

Found (%): C,49.62; H,3.98; N,9.02.

(2)9,1-(Methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid:

To a solution of sodium hydroxide (0.18 g) in water (3 ml) are addeddifluoro[9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxy]borane(0.45 g) and ethanol (15 ml), and the mixture is refluxed for 30minutes. After allowing to cool, acetic acid (1 ml) and water (50 ml)are added to the mixture, and the precipitated crystals are separated byfiltration and washed with water and ethanol in this order andrecrystallized from acetonitrile-ethanol to give the title compound(0.28 g). The obtained compound is identical with9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid obtained in Example 1 in the physical properties thereof.

EXAMPLE 7 Preparation of9,1-(methylimino)methano-7-fluoro-8-[(6R)-1,8-diaza-4-oxabicyclo[4.4.0]deca-8-yl]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound (I) in which Z is(6R)-1,8-diaza-4-oxabicyclo[4.4.0]deca-8-yl]

Diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline4-carboxy]borane (cf. Example 25 hereinafter) (0.8 g) is added to amixture of dimethylsulfoxide (10 ml),(6R)-1,8-diaza-4-oxabicyclo-[4.4.0]decane (cf. Reference Example 21)(0.33 g) and triethylamine (1.5 g), and the mixture is stirred at 60° C.for 5 hours. Dimethylsulfoxide is distilled off under reduced pressure,and to the residue are added acetone (5 ml), conc. hydrochloric acid (3ml) and water (10 ml). The mixture is stirred at 50° C. for one hour.The reaction mixture is concentrated until half volume, and thereto isadded water (10 ml), and the insoluble materials are filtered off. Thefiltrate is washed with chloroform and adjusted to pH 7.5 with aqueoussodium hydroxide, and the precipitated crystals are extracted withchloroform-methanol (30:1 v/v). The extract is dried over anhydroussodium sulfate and concentrated. The residue is recrystallized fromchloroform-ethanol to give the title compound (0.11 g).

M.p. above 300° C.

NMR (DMSO-d₆) δ: 2.2-2.5 (4H, m), 2.7-3.0 (3H, m), 2.8 (3H, s), 3.1-3.4(2H, m), 3.5-3.8 (4H, m), 4.5 (2H, s), 7.6 (1H, s), 7.7 (1H, d,J=12.5Hz), 15.8 (1H, s).

Elementary analysis for C₂₁ H₂₁ N₄ O₄ SF:

Calcd. (%): C,56.75; H,4.76; N,12.60

Found (%): C,56.71; H,4.89; N,12.49.

EXAMPLE 8 Preparation of9,1-(methylimino)methano-7-fluoro-8-(4-oxopiperidino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound (I) in which Z is 4-oxopiperidino]

4-Piperidone hydrochloride monohydrate (0.5 g) is dissolved indimethylsulfoxide (3 ml) and thereto are added diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 25 hereinafter) (0.5 g) and triethylamine (1.6 ml), and themixture is stirred at 60° C. for 5 hours. Triethylamine (1 ml) isadditionally added thereto, and the mixture is further stirred at thesame temperature overnight. The solvent is distilled off under reducedpressure, and to the residue are added acetone (5 ml), water (10 ml) andconc. hydrochloric acid (3 ml), and the mixture is stirred at roomtemperature for one hour. The resulting solid is separated byfiltration, washed with water, acetonitrile and ether in this order togive the title compound (0.36 g). This product is recrystallized fromacetonitrile-dimethylsulfoxide to give a product having the followingphysical properties.

M.p. decomposed at around 290° C.

NMR (DMSO-d₆) δ: 2.5-2.6 (4H, m), 2.8 (3H, s), 3.6-3.7 (4H, m), 4.5 (2H,s), 7.6 (1H, s), 7.7 (1H, d, J=12.5Hz), 15.9 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1696, 1612, 1582, 1462.

Elementary analysis for C₁₉ H₁₆ N₃ O₄ SF.1/4H₂ O:

Calcd. (%): C,56.22; H,4.10; N,10.35

Found (%): C,56.22; H,4.11; N,10.36.

EXAMPLE 9 Preparation of9,1-(methylimino)methano-7-fluoro-8-(4-dimethylaminopiperidino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 4-dimethylaminopiperidino]

A mixture of diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane(cf. Example 25 hereinafter) (0.64 g), 4-dimethylaminopiperidinedihydrochloride (cf. J. Chem. Soc., 3165, 1957) (0.86 g), triethylamine(1.4 g) and dimethylsulfoxide (10 ml) is stirred at 60° C. for 2 hours.The reaction mixture is concentrated to dryness under reduced pressure,and to the residue is added 2N hydrochloric acid (8 ml), and the mixtureis stirred at room temperature for one hour. The precipitated crystal isseparated by filtration, washed with 2N hydrochloric acid and acetoneand then dissolved in water (20 ml). The mixture is adjusted to pH 9.0by adding aqueous sodium hydroxide. The precipitated product isseparated by filtration, washed with water, dried, and thenrecrystallized from chloroform-methanol to give the title compound (0.24g).

M.p. decomposed at around 238° C.

NMR (DMSO-d₆) δ: 1.5-1.6 (2H, m), 1.8-1.9 (2H, m), 2.2 (6H, s), 2.2-2.4(1H, m), 2.8 (3H, s), 3.1-3.2 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H, s), 7.5(1H, s), 7.5 (1H, d, J=12.5Hz), 15.7 (1H, bs).

IR (KBr) ν_(max) cm⁻¹ : 1710, 1614, 1492, 1460.

Elementary analysis for C₂₁ H₂₃ N₄ O₃ SF:

Calcd. (%): C,58.59; H,5.39; N,13.01

Found (%): C,58.44; H,5.40; N,13.13.

EXAMPLE 10 Preparation of9,1-(methylimino)methano-7-fluoro-8-(3-hydroxymethyl-4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid hydrochloride [compound (I) in which Z is3-hydroxymethyl-4-methyl-1-piperazinyl, hydrochloride thereof]

A mixture of diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane(cf. Example 25 hereinafter) (0.87 g),2-hydroxymethyl-1-methylpiperazine diacetate (cf. Reference Example 18)(0.92 g), triethylamine (3.25 ml) and dimethylsulfoxide (16 ml) isstirred at 60° C. for 4 hours. The reaction mixture is concentrated todryness under reduced pressure, and to the residue is added 2Nhydrochloric acid (7 ml) and acetone (14 ml), and the mixture is stirredat room temperature for 30 minutes. The precipitated crystal isseparated by filtration, washed with 2N hydrochloric acid and acetone.The precipitated crystal is recrystallized from 2N hydrochloricacid-methanol to give the title compound (0.45 g).

M.p. decomposed at around 270° C.

NMR (DMSO-d₆ +D₂ O) δ: 2.8 (3H, s), 3.0 (3H, s), 2.3-4.1 (9H, m), 4.5(2H, s), 7.5 (1H, d, J=12.5Hz), 7.5 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1689, 1615, 1463.

Elementary analysis for C₂₀ H₂₁ N₄ O₄ SF.HCl.1H₂ O:

Calcd. (%): C,49.33; H,4.97; N,11.51

Found (%): C,49.23; H,4.88; N,11.41.

EXAMPLE 11 Preparation of 9,1-(methylimino)methano7-fluoro-8-(3-methoxymethyl-4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid hydrochloride [compound (I) in which Z is3-methoxymethyl-4-methyl-1-piperazinyl, hydrochloride thereof]

A mixture of diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 25 hereinafter) (0.63 g),2-methoxymethyl-1-methylpiperazine dihydrochloride (cf. ReferenceExample 19) (0.76 g), triethylamine (1.95 ml) and dimethylsulfoxide (12ml) is stirred at 60° C. for 5 hours. The reaction mixture isconcentrated to dryness under reduced pressure, and to the residue isadded 2N hydrochloric acid (10 ml) and ethanol (20 ml), and the mixtureis stirred under ice cooling for 30 minutes. The precipitated crystal iswashed with ethanol and acetone, and then recrystallized from 2Nhydrochloric acid to give the title compound (0.4 g).

M.p. decomposed at around 248° C.

NMR (D₂ O) δ: 2.7 (3H, s), 3.1 (3H, s), 3.5 (3H, s), 3.4-3.8 (6H, m),3.9-4.1 (1H, m), 4.3 (2H, s), 6.6 (1H, d, J=12Hz), 7.3 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1680, 1616, 1476.

Elementary analysis for C₂₁ H₂₃ N₄ O₄ SF.HCl.3/2H₂ O:

Calcd. (%): C,49.46; H,5.34; N,10.99

Found (%): C,49.48; H,5.43; N,10.97.

EXAMPLE 12 Preparation of9,1-(methylimino)methano-7-fluoro-8-(3-fluoromethyl-4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid hydrochloride [compound (I) in which Z is3-fluoromethyl-4-methyl-1-piperazinyl, hydrochloride thereof]

A mixture of diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane(cf. Example 25 hereinafter) (0.19 g), 2-fluoromethyl-1-methylpiperazinedihydrochloride (cf. Reference Example 20) (0.17 g), triethylamine (0.94ml) and dimethylsulfoxide (5 ml) is stirred at 65° C. for 4 hours. Thereaction mixture is concentrated to dryness under reduced pressure, andto the residue is added 2N hydrochloric acid (6 ml), and the mixture isstirred at room temperature for 30 minutes. The reaction mixture isfiltered, and the filtrate is evaporated to dryness under reducedpressure. To the residue is added ethanol, and the precipitated crystalis separated by filtration. The crystal is recrystallized from 2Nhydrochloric acid-ethanol to give the title compound (72 mg).

M.p. decomposed at around 250° C.

NMR (D₂ O) δ: 2.8 (3H, s), 3.2 (3H, s), 3.5-4.0 (7H, m), 4.4 (2H, s),4.7-5.3 (2H, m), 6.9 (1H, d, J=12Hz), 7.4 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1676, 1616, 1472.

Elemental analysis for C₂₀ H₂₀ N₄ O₃ SF₂.HCl.1H₂ O:

Calcd. (%): C,49.13; H,4.74; N,11.46

Found (%): C,49.30; H,4.72; N,11.09.

EXAMPLE 13 Preparation of9,1-(methylimino)methano-7-fluoro-8-(4-hydroxypiperidino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound (I) in which Z is 4-hydroxypiperidino]

A mixture of diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane(cf. Example 25 hereinafter) (0.5 g), 4-hydroxypiperidine (0.43 g) anddimethylsulfoxide (5 ml) is stirred at room temperature for 19 hours.The reaction mixture is concentrated to dryness under reduced pressure,and to the residue is added 2N hydrochloric acid (6 ml) and acetone (10ml), and the mixture is stirred at room temperature for 30 minutes. Theprecipitated crystal is separated by filtration, washed with water andacetone and then recrystallized from dimethylsulfoxide to give the titlecompound (0.17 g).

M.p. above 280° C.

NMR (DMSO-d₆) δ: 1.5-1.7 (2H, m), 1.8-1.9 (2H, m), 2.8 (3H, s), 3.1-3.3(2H, m), 3.5-3.6 (2H, m), 3.7 (1H, m), 4.5 (2H, s), 4.8 (1H, d, J=4Hz),7.5 (1H, s), 7.6 (1H, d, J=12.5Hz), 15.8 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1693, 1526, 1455.

Elementary analysis for C₁₉ H₁₈ N₄ O₄ SF.1H₂ O:

Calcd. (%): C,54.15; H,4.78; N,9.97

Found (%): C,54.23; H,4.80; N,9.77.

EXAMPLE 14 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound (I) in which Z is 2-methylmorpholino]

9,1-(Methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid (cf. Reference Example 9) (0.3 g) is added to a mixture ofdimethylsulfoxide (3 ml), 2-methylmorpholine hydrochloride (cf.Reference Example 14) (0.15 g) and triethylamine (0.47 g), and themixture is stirred at 95° C. for 15 hours. Dimethylsulfoxide isdistilled off under reduced pressure, and the residue is washed withwater, ethanol and diethyl ether in this order and recrystallized fromacetonitrile-ethanol to give the title compound (0.18 g). This productis identical with9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid obtained in Example 1 in the physical properties.

EXAMPLE 15 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 2-fluoromethylmorpholino]

This compound is prepared by the following two steps.

(1) Ethyl9,1-(methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylate:

Ethyl9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylate(cf. Reference Example 7) (0.5 g), 2-fluoromethylmorpholinehydrochloride (cf. Reference Example 13) (0.28 g) and triethylamine(0.72 g) are added to dimethylsulfoxide (5 ml), and the mixture isstirred at 95° C. for 240 hours. The reaction mixture is concentrated todryness under reduced pressure, and to the residue is added water, andthe mixture is extracted with chloroform. The chloroform layer is washedwith water, dried over anhydrous sodium sulfate and concentrated todryness under reduced pressure. The resulting residue is purified bymedium pressure silica gel column chromatography (eluent,chloroform-methanol=50:1) and recrystallized from ethanol-chloroform togive the title compound (0.16 g).

NMR (CDCl₃) δ: 1.5 (3H, t, J=7Hz), 2.8 (3H, s), 3.2-3.6 (4H, m), 3.8-4.1(3H, m), 4.3 (2H, s), 4.4-4.6 (3H, m), 6.8 (1H, s), 7.9 (1H, d,J=12.5Hz).

(2)9,1-(Methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid:

The above ethyl9,1-(methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylate(0.1 g) and 1N aqueous sodium hydroxide (1.6 ml) are added to ethanol(50 ml), and the mixture is refluxed for 10 hours. The reaction mixtureis concentrated to dryness under reduced pressure, and to the residue isadded water, and the mixture is washed with chloroform. The aqueouslayer is separated and adjusted to pH 6.8 by adding 3N hydrochloricacid. The precipitated crystal is separated by filtration, dried andthen recrystallized from chloroform-ethanol to give the title compound(0.04 g). This product is identical with9,1-(methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo5H-thiazolo[3,2-a]quinoline-4-carboxylic acid obtained in Example 3 inthe physical properties.

EXAMPLE 16 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 2-hydroxymethylmorpholino]

A mixture of difluoro[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 27 hereinafter) (114 g), 2-benzoyloxymethylmorpholinehydrochloride (cf. Reference Example 23) (114 g), triethylamine (157 g)and dimethylsulfoxide (650 ml) is stirred at 70° C. for 24 hours. Theprecipitated crystal is separated by filtration, washed with water andethanol in this order, and thereto are added water (1.5 liter), ethanol(1.5 liter) and sodium hydroxide (61 g), and the mixture is stirred at70° C. for 24 hours. After filtering off the insoluble materials, thefiltrate is adjusted to pH 5 with 6N hydrochloric acid, and theprecipitated crystal is washed with water and acetone in this order andthen recrystallized from dimethylsulfoxide to give the title compound(46 g). This product is identical with9,1-(methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid obtained in Example 2 in the physical properties.

EXAMPLE 17 Preparation of9,1-(methylimino)methano-7-fluoro-8-[(2S)-2-hydroxymethylmorpholino)-5-oxo-5H-triazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is (2S)-2-hydroxymethylmorpholino]

To a mixture of difluoro[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane(cf. Example 27 hereinafter) (0.7 g), (2S)-2-benzoyloxymethylmorpholinehydrochloride (cf. Reference Example 24) (1.0 g) and dimethylsulfoxide(10 ml) is added triethylamine (1.4 ml), and the mixture is stirred at70° C. for 19 hours. The reaction mixture is added to water (30 ml) andthe insoluble materials are separated by filtration and washed withwater and acetone. To the insoluble materials are added 2N aqueoussodium hydroxide (10 ml) and ethanol (10 ml), and the mixture isrefluxed for 3 hours. The reaction mixture is ice-cooled and made acidicwith conc. hydrochloric acid, and the precipitated crystal is separatedby filtration, washed with acetone, and then recrystallized fromdimethylsulfoxide-ethanol to give the title compound (0.3 g).

M.p decomposed at around 254° C.

NMR (DMSO-d₆) δ: 2.8 (3H, s), 3.0-3.1 (1H, m), 3.2-3.8 (7H, m), 3.9-4.0(1H, m), 4.5 (2H, s), 4.8 (1H, t, J=5.5Hz), 7.5 (1H, d, J=12.5Hz), 7.5(1H, s), 15.7 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1690, 1612, 1488, 1476, 1450, 1406.

Elementary analysis for C₁₉ H₁₈ N₃ O₅ SF:

Calcd. (%): C,54.41; H,4.33; N,10.02

Found (%): C,54.20; H,4.41; N,9.87.

[α]_(D) ²¹ +30.6° (c=0.5, 0.1N NaOH)

EXAMPLE 18 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2R)-2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is (2R)-2-hydroxymethylmorpholino]

In the same manner as described in Example 17 except that(2R)-2-benzoyloxymethylmorpholine hydrochloride (cf. Reference Example25) is used instead of (2S)-2-benzoyloxymethylmorpholine hydrochloride,there is prepared the title compound.

M.p. decomposed at around 250° C.

NMR (DMSO-d₆) δ: 2.8 (3H, s), 3.0-3.1 (1H, m), 3.2-3.8 (7H, m), 3.9-4.0(1H, m), 4.5 (2H, s), 4.8 (1H, t, J=5.5Hz), 7.5 (1H, d, J=12.5Hz), 7.5(1H, s), 15.7 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1690, 1612, 1488, 1476, 1450, 1406.

Elementary analysis for C₁₉ H₁₈ N₃ O₅ SF:

Calcd. (%): C,54.41; H,4.33; N,10.02

Found (%): C,54.23; H,4.25; N,9.85.

[α]_(D) ^(<) -29.1° (c=0.5, 0.1N NaOH)

EXAMPLE 19 Preparation of sodium9,1-(methylimino)methano-7-fluoro-8-[2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylate[compound (I) in which Z is 2-hydroxymethylmorpholino, sodium saltthereof]

9,1-(Methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxyicacid (cf. Example 16) (2.2 g) is suspended in water (12.3 ml) andthereto is added 2N aqueous sodium hydroxide (2.7 ml), and the mixtureis heated to dissolve it. To the mixture is added 2N aqueous sodiumhydroxide (15 ml), and the mixture is allowed to stand at roomtemperature. The precipitated crystal is separated by filtration andwashed with 2N aqueous sodium hydroxide and methanol to give the titlecompound (1.3 g).

M.p. above 280° C.

NMR (D₂ O) δ: 2.4 (3H, s), 2.9-3.3 (4H, m), 3.6-4.1 (5H, m), 3.9 (2H,s), 6.9 (1H, s), 7.3 (1H, d, J=13Hz).

IR (KBr) ν_(max) cm⁻¹ : 1607, 1569, 1464.

Elementary analysis for C₁₉ H₁₇ N₃ O₅ SFNa.3/4H₂ O:

Calcd. (%): C,50.16; H,4.10; N,9.24

Found (%): C,50.15; H,4.03; N,9.28.

EXAMPLE 20 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 2-methoxymethylmorpholino]

2-Methoxymethylmorpholine (cf. Reference Example 10) (4.0 g) andtriethylamine (7.1 g) are dissolved in dimethylsulfoxide (40 ml), andthereto is added difluoro[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo-[3,2-a]quinoline-4-carboxy]borane(cf. Example 27 hereinafter) (8.6 g), and the mixture is stirred at 60°C. for 20 hours. To the reaction mixture is added ethanol (160 ml), andthe mixture is stirred at room temperature. The resulting precipitate isseparated by filtration, washed with water and ethanol in this order,and then suspended in a mixture of ethanol (70 ml) and 2N aqueous sodiumhydroxide (35 ml). The mixture is stirred at 100° C. for 1.5 hour. Theinsoluble materials are filtered off, and the filtrate is adjusted toabout pH 6 with 2N hydrochloric acid. The precipitated crystal isseparated by filtration, washed with water and ethanol in this order,and then recrystallized from dimethylsulfoxide-ethanol. The crystal issuspended in ethanol (25 ml), and the mixture is refluxed for 7 hours,cooled till room temperature, and the crystal insoluble in ethanol iscollected to give the title compound (6.5 g).

M.p. decomposed at around 220° C.

NMR (DMSO-d₆) δ: 2.8 (3H, s), 3.0-3.1 (1H, m), 3.2-3.5 (5H, m), 3.3 (3H,s), 3.7-3.8 (2H, m), 3.9-4.0 (1H, m), 4.5 (2H, s), 7.5 (1H, d,J=12.5Hz), 7.5 (1H, s), 15.7 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1694, 1612, 1488.

Elementary analysis for C₂₀ H₂₀ N₃ O₅ SF:

Calcd. (%): C,55.42; H,4.65; N,9.69

Found (%): C,55.39; H,4.75; N,9.54.

EXAMPLE 21 Preparation of9,1-(methylimino)methano-7-fluoro-8-[(2S)-2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylic acid [compound (I) in which Z is(2S)-2-methoxymethylmorpholino]

A mixture of difluoro[9,1-(methylimino)methano7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane(cf. Example 27 hereinafter) (2.5 g), (2S)-2-methoxymethylmorpholinehydrochloride (cf. Reference Example 11) (1.7 g), triethylamine (3.5 ml)and dimethylsulfoxide (30 ml) is stirred at 55°-60° C. for 18 hours. Thereaction mixture is concentrated under reduced pressure, and thereto isadded ethanol (60 ml). The precipitated crystal is separated byfiltration, and thereto are added ethanol (20 ml) and 2N aqueous sodiumhydroxide (15 ml), and the mixture is stirred at 80° C. for 2 hours. Theinsoluble materials are filtered off and the filtrate is adjusted to pH3 with 2N hydrochloric acid. The precipitated crystal is separated byfiltration and recrystallized from dimethylsulfoxide-ethanol to give thetitle compound (1.9 g).

M.p. decomposed at around 220° C.

NMR (DMSO-d₆) δ: 2.8 (3H, s), 3.0-3.1 (1H, m), 3.2-3.5 (5H, m), 3.3 (3H,s), 3.7-3.8 (2H, m), 3.9-4.0 (1H, m), 4.5 (2H, s), 7.6 (1H, s), 7.7 (1H,d, J=12.5Hz), 15.9 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1694, 1614, 1490.

Elementary analysis for C₂₀ H₂₀ N₃ O₅ SF:

Calcd. (%): C,55.42; H,4.65; N,9.69

Found (%): C,55.24; H,4.67; N,9.57.

[α]_(D) ²⁰ +39.5° (c=0.5, 0.1N NaOH).

EXAMPLE 22 Preparation of9,1-(methylimino)methano-7-fluoro-8-[(2R)-2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is (2R)-2-methoxymethylmorpholino]

In the same manner as described in Example 21 except that (2R) 2methoxymethylmorpholine hydrochloride (cf. Reference Example 12) is usedinstead of (2S)-2-methoxymethylmorpholine hydrochloride, there isprepared the title compound.

M.p. decomposed at around 220° C.

NMR (DMSO-d₆) δ: 2.8 (3H, s), 3.0-3.1 (1H, m), 3.2-3.5 (5H, m), 3.3 (3H,s), 3.7-3.8 (2H, m), 3.9-4.0 (2H, m), 4.5 (2H, s), 7.6 (1H, s), 7.7 (1H,d, J=12.5Hz), 15.9 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1694, 1614, 1488.

Elementary analysis for C₂₀ H₂₀ N₃ O₅ SF:

Calcd. (%): C,55.42; H,4.65; N,9.69

Found (%): C,55.47; H,4.72; N,9.66.

[α]_(D) ²⁰ -39.9° (c=0.5, 0.1N NaOH).

EXAMPLE 23 Preparation of sodium9,1-(methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylate[compound (I) in which Z is 2-methoxymethylmorpholino, sodium saltthereof]

9,1-(Methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid (cf. Example 20) (5.0 g) is suspended in water (20 ml), and theretois added 2N aqueous sodium hydroxide (5.9 ml), and the mixture is heatedto dissolve it. 5N aqueous sodium hydroxide (17 ml) is added to themixture, and the mixture is cooled to room temperature. The precipitatedcrystal is separated by filtration and washed with water-acetone (1:1)and acetone in this order to give the title compound (3.0 g).

M.p. above 280° C.

NMR (D₂ O) δ: 2.5 (3H, s), 2.9-3.3 (4H, m), 3.4 (3H, s), 3.5-3.6 (2H,m), 3.7-4.1 (3H, m), 4.0 (2H, s), 6.9 (1H, s), 7.4 (1H, d, J=13Hz).

IR (KBr) ν_(max) cm⁻¹ : 1607, 1569, 1463.

Elementary analysis for C₂₀ H₁₉ N₃ O₅ SFNa.H₂ O:

Calcd. (%): C,50.74; H,4.47; N,8.88

Found (%): C,50.71; H,4.39; N,8.83.

EXAMPLE 24 Preparation of9,1-(methylimino)methano-7-fluoro-8-(2-ethoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid [compound (I) in which Z is 2-ethoxymethylmorpholino]

A mixture of diacetoxy[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane(cf. Example 25 hereinafter) (1.4 g), 2-ethoxymethylmorpholine (cf.Reference Example 22) (0.7 g), triethylamine (1.6 g) anddimethylsulfoxide (40 ml) is stirred at 65° C. for 16 hours. To thereaction mixture is added water, and the insoluble materials areseparated by filtration, and thereto are added acetone (25 ml), conc.hydrochloric acid (8 ml) and water (60 ml), and the mixture is stirredat room temperature for 3 hours. The insoluble materials are separatedby filtration, washed with acetonitrile, and then recrystallized fromdimethylsulfoxide to give the title compound (0.5 g).

M.p. decomposed at around 231° C.

NMR (DMSO-d₆) δ: 1.1 (3H, t, J=7Hz), 2.8 (3H, s), 3.0-3.1 (1H, m),3.2-3.5 (7H, m), 3.7-3.8 (2H, m), 3.9-4.0 (1H, m), 4.5 (2H, s), 7.6 (1H,s), 7.6 (1H, d, J=12.5Hz), 15.8 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1706, 1614, 1494, 1464.

Elementary analysis for C₂₁ H₂₂ N₃ O₅ SF.1/2H₂ O:

Calcd. (%): C,55.25; H,5.08; N,9.20

Found (%): C,55.29; H,5.05; N,9.23.

EXAMPLE 25 Preparation of diacetoxy[9,1-(methylimino)methano7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane[compound (II-1) in which R³ is methyl]

A mixture of boric acid (0.27 g) and acetic anhydride (3 g) is stirredat 75°-80° C. for 50 minutes to give a solution of triacetoxyborane, andthereto is added ethyl9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylate(cf. Reference Example 7) (1.0 g), and the mixture is stirred at 100° C.for 40 minutes. The reaction mixture is allowed to stand at roomtemperature, and the precipitated crystal is separated by filtration,washed with isopropyl ether to give the title compound (1.26 g). Thisproduct is recrystallized from acetonitrile to give the title compoundhaving the following physical properties.

M.p. above 285° C.

NMR (DMSO-d₆) δ: 1.9 (6H, s), 3.3 (3H, d, J=6Hz), 4.8 (2H, d, J=1Hz),7.6 (1H, dd, J=7Hz, J=10Hz), 7.9 (1H, t, J=1Hz).

IR (KBr) ν_(max) cm⁻¹ : 1718, 1697.

Elementary analysis for C₁₈ H₁₃ N₂ O₇ SF₂ B:

Calcd (%): C,48.02; H,2.91; N,6.22

Found (%): C,47.92; H,3.02; N,6.21.

EXAMPLE 26 Preparation of dipropionyloxy[9,1-(methylimino)-methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane[compound (II-1) in which R³ is ethyl]

A mixture of boric acid (1.1 g) and propionic anhydride (8.0 g) isstirred at 75°-80° C. for 50 minutes to give a solution oftripropionyloxyborane, and thereto is added ethyl9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylate(cf. Reference Example 7) (4.0 g), and the mixture is refluxed withstirring for 40 minutes. The reaction mixture is allowed to stand atroom temperature, and the precipitated crystal is separated byfiltration, washed with isopropyl ether, and then recrystallized fromacetonitrile to give the title compound (5.1 g).

M.p. decomposed at around 256° C.

NMR (DMSO-d₆) δ: 0.9 (6H, t, J=7.5Hz), 2.2 (4H, q, J=7.5Hz), 3.3 (3H,s), 4.8 (2H, s), 7.6 (1H, dd, J=10Hz, J=7Hz), 8.0 (1H, s).

IR (KBr) ν_(max) cm⁻¹ : 1724, 1702, 1534.

Elementary analysis for C₂₀ H₁₇ N₂ O₇ SF₂ B:

Calcd. (%): C,50.23; H,3.58; N,5.86

Found (%): C,50.21; H,3.62; N,5.92.

EXAMPLE 27 Preparation of difluoro[9,1-(methylimino)methano7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]borane[compound (II-2)]

To diethyl(5-methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]quinoxalin-1-ylidene)malonate(cf. Reference Example 6) (2.0 g) are added acetic anhydride (6 ml) andborone trifluoride-etherate complex (0.72 ml), and the mixture isstirred at 100° C. for 8 hours. After allowing to cool, the precipitatedcrystal is separated by filtration, washed with acetic anhydride andisopropyl ether in this order to give the title compound (1.66 g).

M.p. above 280° C.

NMR (DMSO-d₆) δ: 3.4 (3H, d, J=6Hz), 4.8 (2H, d, J=1Hz), 7.7 (1H, dd,J=7Hz, J=10Hz), 8.0 (1H, t, J=1Hz).

IR (KBr) ν_(max) cm⁻¹ : 1695, 1533, 1494, 1471, 1462, 1410.

Elementary analysis for C₁₄ H₇ N₂ O₃ SF₄ B:

Calcd. (%): C,45.43: H,1.91: N,7.57

Found (%): C,45.41: H,2.15: N,7.56.

EXAMPLE 28 Preparation of difluoro [9,1(methylimino)methano7,8-difluoro-5-oxo-5H-thiazolo[3,2 a]quinoline4-carboxy]-borane [compound (I) in which R is difluoroboryl]

Ammonium fluoroborate (1.06 g) is added to acetic anhydride (10 ml), andthe mixture is stirred at 100° C. for one hour. To the mixture is addeddiethyl(5-methyl-6,7-difluoro-1H,4H-thiazolo[3,4-a]quinoxalin-1-ylidene)malonate(cf. Reference Example 6) (2.0 g), and the mixture is stirred at thesame temperature as above for 5 hours. The reaction mixture is allowedto stand at room temperature, and the precipitated crystal is separatedby filtration, washed with ethyl acetate, water and acetone in thisorder to give the title compound (1.7 g). This product is identical withdifluoro[9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]boraneobtained in Example 27 in the physical properties.

EXAMPLE 29 Preparation of Tablets

Tablets each containing 100 mg of9,1-(methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quionoline-4-carboxylicacid [compound of Example 3] are prepared as follows:

    ______________________________________                                        (Formula)                                                                     Ingredients              Part by weight                                       ______________________________________                                        The active ingredient (compound of Example 3)                                                          100                                                  Corn starch              46                                                   Microcrystalline cellulose                                                                             98                                                   Hydroxypropyl cellulose   2                                                   Magnesium stearate        4                                                   ______________________________________                                    

(Procedure)

To a mixture of the active ingredient, corn starch and microcrystallinecellulose is added a solution of hydroxypropyl cellulose in water (50parts by weight) and the mixture is kneaded well. The kneaded mixture ispassed through a mesh to produce granules. After drying the granules,magnesium stearate is mixed with the granules and the mixture istabletted by a conventional method to give tablets (each 250 mg).

EXAMPLE 30 Preparation of Granules

Granules each containing9,1-(methylimino)methano7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 3] (200 mg) per 500 mg granules are preparedas follows:

    ______________________________________                                        (Formula)                                                                     Ingredients              Part by weight                                       ______________________________________                                        The active ingredient (compound of Example 3)                                                          200                                                  Lactose                  185                                                  Corn starch              109                                                  Hydroxypropyl cellulose   6                                                   ______________________________________                                    

(Procedure)

To a mixture of the active ingredient, lactose and corn starch is addeda solution of hydroxypropyl cellulose in water (120 parts by weight) andthe mixture is kneaded well. The kneaded mixture is passed through a No.20 mesh sieve to produce granules. The granules are dried and passedthrough a sieve of desired size to yield the granules.

EXAMPLE 31 Preparation of Capsules

Capsules each containing 100 mg of9,1-(methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 3] are prepared as follows:

    ______________________________________                                        (Formula)                                                                     Ingredients              Part by weight                                       ______________________________________                                        The active ingredient (compound of Example 3)                                                          100                                                  Lactose                  35                                                   Corn starch              60                                                   Magnesium stearate        5                                                   ______________________________________                                    

(Procedure)

All the above ingredients were mixed throughly and the resulting powderymixture was packed into gelatin capsules in each amount of 200 mg.

EXAMPLES 32-34

Preparation of Tablets

Tablets each containing 100 mg of9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 1],9,1-(methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid [compound of Example2], or9,1-(methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid (compound of Example 20) are prepared by the procedure as describedin Example 29 except that the compound of Example 1, 2 or 20 is employedin place of the compound of Example 3 as the active ingredient.

EXAMPLES 35-37 Preparation of Granules

Granules each containing9,1-(methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylicacid hydrochloride [compound of Example 1],9,1-(methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid [compound of Example 2] or9,1-(methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino) 5oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid [compound of Example20] is prepared by the procedure as described in Example 30 except thatthe compound of Example 1, 2 or 20 is employed in place of the compoundof Example 3 as the active ingredient.

What is claimed is:
 1. A quinolinecarboxylic acid derivative of theformula: ##STR25## wherein ##STR26## in which R¹ is hydrogen, chlorine,fluorine hydroxy, methoxy or ethoxy, or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1, wherein Z is##STR27## (where R¹ is hydrogen, chlorine, fluorine, hydroxy, methoxy orethoxy, or a pharmaceutically acceptable salt thereof.
 3. The compoundaccording to claim 1, wherein Z is ##STR28## or a pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 1, which isa member selected from the followingcompounds:9,1-(Methylimino)methano-7-fluoro-8-(2-methylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof;9,1-(Methylimino)methano-7-fluoro-8-(2-hydroxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof;9,1-(Methylimino)methano-7-fluoro-8-(2-fluoromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof;9,1-(Methylimino)methano-7-fluoro-8-(2-chloromethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof;9,1-(Methylimino)methano-7-fluoro-8-(2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof;9,1-(Methylimino)methano-7-fluoro-8-[(6R)-1,8-diaza-4-oxabicyclo[4.4.0]deca-8-yl]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof; 9.1-(Methylimino)methano-7-fluoro-8-[(2S)-2-hydroxymethylmorpholino]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable saltthereof;9,1-(Methylimino)methano-7-fluoro-8-[(2R)-2-hydroxymethylmorpholino]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof;9,1-(Methylimino)methano-7-fluoro-8-[(2S)-2-methoxymethylmorpholino]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof;9,1-(Methylimino)methano-7-fluoro-8-[(2R)-2-methoxymethylmorpholino]-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof;9,1-(Methylimino)methano-7-fluoro-8-(2-ethoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 5. An antibacterialcomposition comprising as an active ingredient an effective amount of aquinolinecarboxylic acid derivative of the formula: ##STR29## wherein##STR30## in which R¹ is hydrogen, chlorine, fluorine, hydroxy, methoxyor ethoxy, or a pharmaceutically acceptable salt thereof, in admixturewith pharmaceutically acceptable carrier or diluent.
 6. The compositionof claim 5, which is in a form for oral administration.
 7. A method forproviding an antibacterial effect to a subject need thereof, comprisingadministering to the subject an antibacterially-effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof.
 8. The method of claim 7, wherein the compound is administeredorally.